library(dplyr)
library(knitr)
select_top_genes <- function(inversion,type){
  trans <- sig_genes_trans[which(sig_genes_trans$Inversion==inversion & sig_genes_trans$Type_analysis==type),]
  selecttrans <- data.frame(Inversion=character(),
                            Type_analysis=character(), 
                            Transcript=character(),
                            Location=character(),
                            Gene_Symbol=character(),
                            model=character(),
                            adj.p.value=numeric(),
                            DiffLevene_logFC=numeric(),
                            stringsAsFactors=FALSE)
  for (transcript in trans$Transcript){
    transcriptsDF <- trans[which(trans$Transcript==transcript),]
    bestmodel <- transcriptsDF[which.min(transcriptsDF$adj.p.value),]
    selecttrans <- rbind(selecttrans,bestmodel)
  }
  selecttrans <- selecttrans %>% distinct()
  return(selecttrans)
}
select_top_cpgs <- function(inversion,type){
  methy <- sig_cpgs_methy[which(sig_cpgs_methy$Inversion==inversion & sig_cpgs_methy$Type_analysis==type),]
  selectmethy <- data.frame(Inversion=character(),
                            Type_analysis=character(), 
                            CpG=character(),
                            Location=character(),
                            Gene_Symbol=character(),
                            model=character(),
                            adj.p.value=numeric(),
                            DiffLevene_logFC=numeric(),
                            stringsAsFactors=FALSE)
  for (cpg in methy$CpG){
    cpgsDF <- methy[which(methy$CpG==cpg),]
    bestmodel <- cpgsDF[which.min(cpgsDF$adj.p.value),]
    selectmethy <- rbind(selectmethy,bestmodel)
  }
  selectmethy <- selectmethy %>% distinct()
  return(selectmethy)
}

1 Association between inversion genotypes and human traits

Table 1 shows the associations between polymorphic inversions and obesity-related traits with a p-value below 0.0227. In the case of neurological traits, Table 2 displays the associations with a p-value below 0.01.


Table 1: Significant associations between genomic inversions and obesity-related traits
Phenotype Phenotype_abrev Inversion model p.value
hs_chol_cperc_None_v2 Total Cholesterol 8p23.1 Dominant 0.0197885
hs_chol_cperc_None_v2 Total Cholesterol 8p23.1 Additive 0.0091123
hs_phospho_c_None Phospholipids 8p23.1 Dominant 0.0197029
hs_phospho_cperc_None_v2 Phospholipids 8p23.1 Dominant 0.0197029
hs_totchol_c_None Total Cholesterol 8p23.1 Dominant 0.0197885
hs_totchol_c_None Total Cholesterol 8p23.1 Additive 0.0091123
e3_bwc_None Birth weight 8p23.1 Recessive 0.0107270
e3_pi_None Ponderal index 8p23.1 Recessive 0.0135604
hs_creatinine_c_None Creatinine 16p11.2 Dominant 0.0156135
hs_creatinine_cg_None Creatinine 16p11.2 Dominant 0.0156135

Table 2: Significant associations between genomic inversions and neurological traits
Phenotype Phenotype_abrev Inversion model p.value
hs_Esc_AD NA 16p11.2 Recessive 0.0085207
hs_nhitcolors1 number of hits colors 1-back 16p11.2 Dominant 0.0063459
hs_nfacolors1 number of false alarms colors 1-back 17q21.31 Additive 0.0095820
hs_nmisscolors1 number of miss colors 1-back 17q21.31 Dominant 0.0032456
hs_nmisscolors1 number of miss colors 1-back 17q21.31 Additive 0.0031775
hs_nhitcolors3 number of hits colors 3-back 17q21.31 Additive 0.0079295
hs_accuracy_colors1 Percentage of correct responses (hits and correct rejections) colors 1-back 17q21.31 Dominant 0.0036305
hs_accuracy_colors1 Percentage of correct responses (hits and correct rejections) colors 1-back 17q21.31 Additive 0.0018287
hs_dcolors1 detectability colors 1-back 17q21.31 Dominant 0.0042137
hs_dcolors1 detectability colors 1-back 17q21.31 Additive 0.0027919
hs_accuracy_numeros3 Percentage of correct responses (hits and correct rejections) numbers 3-back 17q21.31 Recessive 0.0022171
hs_dnumeros3 detectability numbers 3-back 17q21.31 Recessive 0.0008315
hs_sum_non_domHand Sum of the 2 trials nondominant hand 17q21.31 Dominant 0.0018789
hs_sum_non_domHand Sum of the 2 trials nondominant hand 17q21.31 Additive 0.0015241

2 Mediation of mean differentially expressed genes

2.1 Mean Differential Analysis (MDA)

2.1.1 MDA for transcriptome

Inversion 8p23.1

The significant MDE genes for inversion 8p23.1 are shown in Table 3. Figures 1, 2, 3, and 4 include panels of box-plots illustrating the effect of inversion status on the gene expression. Finally, the enrichment analysis of these genes has been performed and the results are presented in Figure 5.


Table 3: Significant mean differentially expressed genes according to inversion 8p23.1 genotype
Inversion Type_analysis Transcript Location Gene_Symbol model adj.p.value DiffLevene_logFC
8p23.1 Mean TC08000087.hg.1 chr8:11351510-11422113 BLK additive 0.0000000 -0.1227452
8p23.1 Mean TC08000093.hg.1 chr8:11653082-11696818 FDFT1 additive 0.0000000 0.0832526
8p23.1 Mean TC08000975.hg.1 chr8:11278972-11324276 FAM167A additive 0.0000000 0.0762627
8p23.1 Mean TC08000937.hg.1 chr8:8095196-8102189 ALG1L13P additive 0.0000000 0.0875426
8p23.1 Mean TC08000056.hg.1 chr8:8086092-8102387 FAM86B3P additive 0.0000000 -0.0303383
8p23.1 Mean TC08000099.hg.1 chr8:12051976-12053789 FAM85A additive 0.0000000 0.1051436
8p23.1 Mean TC08000067.hg.1 chr8:9046509-9060364 BC017578 additive 0.0000000 0.0376679
8p23.1 Mean TC08002596.hg.1 chr8:12294522-12424423 LOC100506990 additive 0.0000000 0.0464301
8p23.1 Mean TC08001804.hg.1 chr8:11973291-12482364 LOC100506990;FAM66D;FAM66A additive 0.0000000 0.0358563
8p23.1 Mean TC08000085.hg.1 chr8:11188397-11189717 SLC35G5 additive 0.0000000 -0.0532857
8p23.1 Mean TC08000988.hg.1 chr8:12039605-12051642 FAM86B1 additive 0.0000000 -0.0204385
8p23.1 Mean TC08000091.hg.1 chr8:11627172-11644855 NEIL2 additive 0.0000002 0.0222975
8p23.1 Mean TC08000071.hg.1 chr8:9911778-10286401 MSRA additive 0.0000032 -0.0182060
8p23.1 Mean TC08000995.hg.1 chr8:12282913-12293915 FAM86B2;FAM86B1 additive 0.0000068 -0.0184390
8p23.1 Mean TC08000063.hg.1 chr8:8859657-8974256 ERI1 additive 0.0000144 0.0185050
8p23.1 Mean TC08000938.hg.1 chr8:8175258-8244008 SGK223 additive 0.0000190 0.0357897
8p23.1 Mean TC08000935.hg.1 chr8:7992174-8085385 FAM85B additive 0.0002706 0.0300686
8p23.1 Mean TC08002222.hg.1 chr8:10980891-10982327 C8orf15 recessive 0.0004446 0.0690433
8p23.1 Mean TC08002231.hg.1 chr8:12282231-12282893 AK308439 additive 0.0024369 -0.0359307
8p23.1 Mean TC08000069.hg.1 chr8:9413422-9639856 TNKS additive 0.0036524 -0.0115602
8p23.1 Mean TC08000994.hg.1 chr8:12282231-12282893 AK308439 additive 0.0077124 -0.0323173
Box-plot representation for the mean differentially expressed genes in inversion 8p23.1 (1). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Figure 1: Box-plot representation for the mean differentially expressed genes in inversion 8p23.1 (1)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Box-plot representation for the mean differentially expressed genes in inversion 8p23.1 (2). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Figure 2: Box-plot representation for the mean differentially expressed genes in inversion 8p23.1 (2)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Box-plot representation for the mean differentially expressed genes in inversion 8p23.1 (3). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Figure 3: Box-plot representation for the mean differentially expressed genes in inversion 8p23.1 (3)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Box-plot representation for the mean differentially expressed genes in inversion 8p23.1 (4). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Figure 4: Box-plot representation for the mean differentially expressed genes in inversion 8p23.1 (4)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Enrichment analysis results for the mean differential expressed (DE) genes for inversion 8p23.1. The colour depends on the p-value adjusted and the size of the dot indicates the number of counts. A) Results using KEGG database; B) Results using DisGeNET database; c) Results using GO database.

Figure 5: Enrichment analysis results for the mean differential expressed (DE) genes for inversion 8p23.1
The colour depends on the p-value adjusted and the size of the dot indicates the number of counts. A) Results using KEGG database; B) Results using DisGeNET database; c) Results using GO database.

Inversion 16p11.2

In the case of the 16p11.2 region, Table 4 reveals the MDE genes, and Figures 6, 7, 8 show the distribution of the gene expression according to the inversion status. The results of the enrichment analysis are displayed in Figure 9.


Table 4: Significant mean differentially expressed genes according to inversion 16p11.2 genotype
Inversion Type_analysis Transcript Location Gene_Symbol model adj.p.value DiffLevene_logFC
16p11.2 Mean TC16000994.hg.1 chr16:28853732-28857729 TUFM;MIR4721 additive 0.0000000 0.1590659
16p11.2 Mean TC16000303.hg.1 chr16:28565247-28603111 CCDC101 additive 0.0000000 -0.1367914
16p11.2 Mean TC16000314.hg.1 chr16:28986093-29002104 LAT;SPNS1 additive 0.0000000 0.0461986
16p11.2 Mean TC16000986.hg.1 chr16:28390900-28437775 EIF3CL;EIF3C dominant 0.0000000 0.2095409
16p11.2 Mean TC16000305.hg.1 chr16:28699879-28747053 EIF3C;EIF3CL additive 0.0000000 0.1551929
16p11.2 Mean TC16000300.hg.1 chr16:28303840-28335170 SBK1 additive 0.0000000 -0.0644445
16p11.2 Mean TC16000991.hg.1 chr16:28616903-28634907 SULT1A1 additive 0.0000035 -0.0657185
16p11.2 Mean TC16002064.hg.1 chr16:28477974-28503623 CLN3 recessive 0.0001750 0.0252059
16p11.2 Mean TC16000306.hg.1 chr16:28763108-29064044 NPIPL1;NPIPB9 additive 0.0020281 0.0197922
16p11.2 Mean TC16000985.hg.1 chr16:28353876-28374829 NPIPL1;NPIPB6 additive 0.0056078 0.0183324
16p11.2 Mean TC16000990.hg.1 chr16:28603264-28608430 SULT1A2 dominant 0.0036653 -0.0408426
16p11.2 Mean TC16002063.hg.1 chr16:28467693-28481868 NPIPB7;NPIPL1 additive 0.0131460 0.0178750
16p11.2 Mean TC16000304.hg.1 chr16:28648975-28670003 NPIPB8;NPIPL1 dominant 0.0198395 0.0254312
16p11.2 Mean TC16001830.hg.1 chr16:29114978-29119032 AK075019 additive 0.0217447 0.0195208
16p11.2 Mean TC16000307.hg.1 chr16:28814097-28829149 AK125489 dominant 0.0108139 -0.0333196
Box-plot representation for the mean differentially expressed genes in inversion 16p11.2 (1). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Figure 6: Box-plot representation for the mean differentially expressed genes in inversion 16p11.2 (1)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Box-plot representation for the mean differentially expressed genes in inversion 16p11.2 (2). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Figure 7: Box-plot representation for the mean differentially expressed genes in inversion 16p11.2 (2)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Box-plot representation for the mean differentially expressed genes in inversion 16p11.2 (3). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Figure 8: Box-plot representation for the mean differentially expressed genes in inversion 16p11.2 (3)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Enrichment analysis results for the mean differentially expressed (DE) genes for inversion 16p11.2. The colour depends on the p-value adjusted and the size of the dot indicates the number of counts. A) Results using KEGG database; B) Results using DisGeNET database; c) Results using GO database.

Figure 9: Enrichment analysis results for the mean differentially expressed (DE) genes for inversion 16p11.2
The colour depends on the p-value adjusted and the size of the dot indicates the number of counts. A) Results using KEGG database; B) Results using DisGeNET database; c) Results using GO database.

Inversion 17q21.31

The polymorphic inversion 17q21.31 changes the mean expression of the genes that appear in Table 5 and in Figures 10 and 11. The enrichment analysis did not revealed any overrepresented function or disease.


Table 5: Significant mean differentially expressed genes according to inversion 17q21.31 genotype
Inversion Type_analysis Transcript Location Gene_Symbol model adj.p.value DiffLevene_logFC
17q21.31 Mean TC17001604.hg.1 chr17:43590734-43593064 AX747150;LRRC37A4P dominant 0.0000201 0.1043619
17q21.31 Mean TC17000597.hg.1 chr17:44370099-44415160 LRRC37A dominant 0.0000083 0.0749635
17q21.31 Mean TC17002671.hg.1 chr17:43593073-43593494 DQ588732 additive 0.0007577 0.0580581
17q21.31 Mean TC17000599.hg.1 chr17:44590076-44633016 LRRC37A2 dominant 0.0000479 0.0853964
17q21.31 Mean TC17001605.hg.1 chr17:43593073-43593494 DQ588732 additive 0.0009355 0.0548442
17q21.31 Mean TC17001603.hg.1 chr17:43578684-43597889 LRRC37A4P recessive 0.0001806 -0.1378019
17q21.31 Mean TC17001608.hg.1 chr17:43677491-43679748 LOC644172 recessive 0.0066951 -0.1062447
17q21.31 Mean TC17000596.hg.1 chr17:44270939-44274089 KANSL1-AS1 dominant 0.0134399 0.0531628
Box-plot representation for the mean differentially expressed genes in inversion 17q21.31 (1). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Figure 10: Box-plot representation for the mean differentially expressed genes in inversion 17q21.31 (1)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Box-plot representation for the mean differentially expressed genes in inversion 17q21.31 (2). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Figure 11: Box-plot representation for the mean differentially expressed genes in inversion 17q21.31 (2)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

2.1.2 MDA for methylome

Inversion 8p23.1

The MDM CpG sites for inversion 8p23.1 are shown in Table 6 and their respective genes are enriched in functions revealed in Figure 12.


Table 6: Significant mean differentially methylated CpG sites according to inversion 8p23.1 genotype
Inversion Type_analysis CpG Location Gene_Symbol model adj.p.value DiffLevene_logFC
8p23.1 Mean cg12568669 chr8:11666485 FDFT1 additive 0.0000000 -0.0611847
8p23.1 Mean cg11548083 chr8:10208156 MSRA additive 0.0000000 0.0282089
8p23.1 Mean cg12940923 chr8:10282607 MSRA additive 0.0000000 0.0310833
8p23.1 Mean cg01383082 chr8:11323474 FAM167A additive 0.0000000 -0.0294784
8p23.1 Mean cg02711665 chr8:11664728 FDFT1 additive 0.0000000 0.0264331
8p23.1 Mean cg11465442 chr8:11832261 DEFB136 additive 0.0000000 0.0222735
8p23.1 Mean cg12395012 chr8:11607386 GATA4 additive 0.0000000 -0.0282734
8p23.1 Mean cg20987067 chr8:8747297 MFHAS1 additive 0.0000000 0.0229878
8p23.1 Mean cg20449619 chr8:10581784 SOX7 additive 0.0000000 0.0314587
8p23.1 Mean cg02319733 chr8:10282549 MSRA additive 0.0000000 0.0153225
8p23.1 Mean cg08265495 chr8:11212668 TDH additive 0.0000000 0.0325432
8p23.1 Mean cg06620390 chr8:10192943 MSRA additive 0.0000000 0.0209409
8p23.1 Mean cg00629382 chr8:10268916 MSRA additive 0.0000000 0.0179638
8p23.1 Mean cg08841257 chr8:10191002 MSRA additive 0.0000000 0.0249395
8p23.1 Mean cg02771117 chr8:11279352 FAM167A;C8orf12 additive 0.0000000 0.0466767
8p23.1 Mean cg13601595 chr8:10468038 RP1L1 additive 0.0000000 -0.0143857
8p23.1 Mean cg21701351 chr8:11374773 BLK additive 0.0000000 -0.0266353
8p23.1 Mean cg10596361 chr8:10907750 XKR6 additive 0.0000000 0.0274953
8p23.1 Mean cg20497631 chr8:8647440 MFHAS1 additive 0.0000000 0.0245341
8p23.1 Mean cg21725652 chr8:10918152 XKR6 additive 0.0000000 0.0259479
8p23.1 Mean cg15426459 chr8:11813211 additive 0.0000000 0.0248835
8p23.1 Mean cg00184457 chr8:8946301 additive 0.0000000 0.0273532
8p23.1 Mean cg05460571 chr8:8630364 additive 0.0000000 0.0124244
8p23.1 Mean cg21915799 chr8:10282809 MSRA additive 0.0000000 0.0209622
8p23.1 Mean cg03399933 chr8:11205972 TDH additive 0.0000000 -0.0293170
8p23.1 Mean cg02840367 chr8:11660030 FDFT1 additive 0.0000000 -0.0421582
8p23.1 Mean cg27000590 chr8:8182003 PRAGMIN additive 0.0000000 -0.0175409
8p23.1 Mean cg12840336 chr8:11422730 additive 0.0000000 -0.0266457
8p23.1 Mean cg14919250 chr8:10917293 XKR6 additive 0.0000000 0.0254535
8p23.1 Mean cg16038868 chr8:10192619 MSRA additive 0.0000000 0.0144216
8p23.1 Mean cg01601443 chr8:10581988 SOX7 additive 0.0000000 0.0172787
8p23.1 Mean cg04654363 chr8:8581213 additive 0.0000000 -0.0121287
8p23.1 Mean cg03533216 chr8:11206009 TDH additive 0.0000000 -0.0187243
8p23.1 Mean cg16810626 chr8:11594003 GATA4 additive 0.0000000 0.0331651
8p23.1 Mean cg16331727 chr8:11630219 NEIL2 additive 0.0000000 -0.0240012
8p23.1 Mean cg20009332 chr8:10489118 RP1L1 additive 0.0000000 0.0162381
8p23.1 Mean cg05753693 chr8:10192930 MSRA additive 0.0000000 0.0102163
8p23.1 Mean cg06819296 chr8:10982668 XKR6 additive 0.0000000 -0.0120234
8p23.1 Mean cg14257676 chr8:10192642 MSRA additive 0.0000000 0.0132926
8p23.1 Mean cg04989185 chr8:9790928 additive 0.0000000 -0.0199113
8p23.1 Mean cg18303581 chr8:8239485 PRAGMIN additive 0.0000000 0.0106966
8p23.1 Mean cg10597661 chr8:8256332 additive 0.0000000 0.0117799
8p23.1 Mean cg00074818 chr8:8560427 CLDN23 additive 0.0000000 0.0150779
8p23.1 Mean cg09141662 chr8:11206023 TDH additive 0.0000000 -0.0131885
8p23.1 Mean cg12792075 chr8:12244565 FAM66A dominant 0.0000000 0.0722159
8p23.1 Mean cg00569813 chr8:8483549 additive 0.0000000 0.0093748
8p23.1 Mean cg11269159 chr8:9788745 additive 0.0000000 -0.0120478
8p23.1 Mean cg26288502 chr8:10421582 additive 0.0000000 -0.0130067
8p23.1 Mean cg10657228 chr8:10386222 T-SP1 additive 0.0000000 -0.0264181
8p23.1 Mean cg27127887 chr8:11831823 DEFB136 additive 0.0000000 0.0111173
8p23.1 Mean cg17475643 chr8:10261972 MSRA additive 0.0000000 -0.0106970
8p23.1 Mean cg09528494 chr8:11338675 additive 0.0000000 0.0107421
8p23.1 Mean cg02520399 chr8:8168661 additive 0.0000000 0.0118909
8p23.1 Mean cg16513326 chr8:10877312 XKR6 additive 0.0000000 0.0090250
8p23.1 Mean cg06671706 chr8:8559999 CLDN23 additive 0.0000000 0.0281511
8p23.1 Mean cg14329976 chr8:11627812 NEIL2 additive 0.0000000 0.0209233
8p23.1 Mean cg11302791 chr8:10635419 PINX1 additive 0.0000000 -0.0184717
8p23.1 Mean cg18237548 chr8:8860050 ERI1 additive 0.0000000 -0.0154080
8p23.1 Mean cg06240162 chr8:11142829 MTMR9 additive 0.0000000 0.0138272
8p23.1 Mean cg22799963 chr8:11536778 additive 0.0000000 0.0115425
8p23.1 Mean cg23217680 chr8:9029456 additive 0.0000000 -0.0182175
8p23.1 Mean cg10039590 chr8:8859974 ERI1 additive 0.0000000 -0.0097582
8p23.1 Mean cg26075742 chr8:10753237 additive 0.0000000 0.0093203
8p23.1 Mean cg01273802 chr8:10871371 XKR6 additive 0.0000000 0.0085097
8p23.1 Mean cg27280535 chr8:8746679 MFHAS1 additive 0.0000000 0.0112203
8p23.1 Mean cg16871763 chr8:11537909 additive 0.0000000 0.0096141
8p23.1 Mean cg13293535 chr8:11597251 GATA4 additive 0.0000000 -0.0277988
8p23.1 Mean cg11784887 chr8:8729819 MFHAS1 additive 0.0000000 -0.0135406
8p23.1 Mean cg16232071 chr8:10907718 XKR6 additive 0.0000000 -0.0140330
8p23.1 Mean cg01558037 chr8:10772570 XKR6 additive 0.0000000 0.0125076
8p23.1 Mean cg23007325 chr8:10924633 XKR6 additive 0.0000000 0.0146918
8p23.1 Mean cg18461678 chr8:10472980 RP1L1 additive 0.0000000 0.0091869
8p23.1 Mean cg12618270 chr8:8667411 MFHAS1 additive 0.0000000 0.0090570
8p23.1 Mean cg04880278 chr8:11597172 GATA4 additive 0.0000000 -0.0127338
8p23.1 Mean cg24861686 chr8:11418058 BLK additive 0.0000000 -0.0095165
8p23.1 Mean cg26552638 chr8:10875534 XKR6 additive 0.0000000 0.0104856
8p23.1 Mean cg03617420 chr8:10916666 XKR6 additive 0.0000000 -0.0063183
8p23.1 Mean cg01617280 chr8:8745938 MFHAS1 additive 0.0000000 0.0125593
8p23.1 Mean cg03059247 chr8:11287657 C8orf12;FAM167A additive 0.0000000 -0.0059564
8p23.1 Mean cg00718039 chr8:8681339 MFHAS1 additive 0.0000000 -0.0075934
8p23.1 Mean cg17329886 chr8:10513629 RP1L1 additive 0.0000000 -0.0151366
8p23.1 Mean cg24727203 chr8:9007933 PPP1R3B additive 0.0000000 0.0074513
8p23.1 Mean cg09697033 chr8:10929599 XKR6 additive 0.0000000 0.0116283
8p23.1 Mean cg01048752 chr8:10001523 MSRA additive 0.0000000 0.0099567
8p23.1 Mean cg12637676 chr8:11587161 GATA4 additive 0.0000000 0.0103141
8p23.1 Mean cg17167536 chr8:10906938 XKR6 additive 0.0000000 0.0109941
8p23.1 Mean cg01402994 chr8:11665969 FDFT1 additive 0.0000000 -0.0108182
8p23.1 Mean cg19746780 chr8:11540602 additive 0.0000000 0.0066767
8p23.1 Mean cg09768257 chr8:11628346 NEIL2 additive 0.0000000 0.0117662
8p23.1 Mean cg25092989 chr8:10932494 XKR6 additive 0.0000000 0.0065117
8p23.1 Mean cg04335815 chr8:11417517 BLK additive 0.0000000 -0.0072381
8p23.1 Mean cg04756296 chr8:8859877 ERI1 additive 0.0000000 -0.0095963
8p23.1 Mean cg12641275 chr8:11411487 BLK additive 0.0000000 -0.0103945
8p23.1 Mean cg15633056 chr8:10236882 MSRA additive 0.0000001 0.0095738
8p23.1 Mean cg02309752 chr8:11835607 recessive 0.0000001 0.0153665
8p23.1 Mean cg24036517 chr8:10585394 SOX7 additive 0.0000001 0.0084586
8p23.1 Mean cg18217048 chr8:9742024 additive 0.0000001 -0.0101426
8p23.1 Mean cg10414350 chr8:10210282 MSRA additive 0.0000002 0.0079841
8p23.1 Mean cg10764196 chr8:10489270 RP1L1 additive 0.0000002 0.0115183
8p23.1 Mean cg24387126 chr8:11617293 GATA4 additive 0.0000002 -0.0070235
8p23.1 Mean cg01613189 chr8:10875246 XKR6 additive 0.0000002 0.0067084
8p23.1 Mean cg07593977 chr8:11735419 additive 0.0000003 -0.0090978
8p23.1 Mean cg21497594 chr8:11366745 BLK additive 0.0000003 0.0086188
8p23.1 Mean cg27034466 chr8:11760342 additive 0.0000004 0.0044595
8p23.1 Mean cg02525722 chr8:10404760 additive 0.0000004 0.0272121
8p23.1 Mean cg01716419 chr8:11759663 additive 0.0000005 -0.0051488
8p23.1 Mean cg10613815 chr8:11283299 C8orf12;FAM167A additive 0.0000006 0.0167254
8p23.1 Mean cg21088119 chr8:11251471 C8orf12 additive 0.0000006 -0.0052887
8p23.1 Mean cg16299576 chr8:10872819 XKR6 additive 0.0000010 0.0074867
8p23.1 Mean cg20671920 chr8:10586678 SOX7 additive 0.0000010 -0.0086875
8p23.1 Mean cg01535726 chr8:9911482 MSRA additive 0.0000016 0.0069738
8p23.1 Mean cg06182099 chr8:9789639 additive 0.0000024 -0.0089267
8p23.1 Mean cg19882315 chr8:11351846 BLK additive 0.0000029 0.0060957
8p23.1 Mean cg20902975 chr8:11138403 additive 0.0000041 0.0048105
8p23.1 Mean cg10805511 chr8:11843816 additive 0.0000043 0.0097914
8p23.1 Mean cg13963446 chr8:11666017 FDFT1 additive 0.0000058 -0.0073173
8p23.1 Mean cg26161004 chr8:11413186 BLK additive 0.0000062 0.0054195
8p23.1 Mean cg22974952 chr8:7212700 FAM66B additive 0.0000063 -0.0138711
8p23.1 Mean cg27655954 chr8:10753160 additive 0.0000081 0.0068565
8p23.1 Mean cg07755718 chr8:8639450 additive 0.0000089 0.0072381
8p23.1 Mean cg06292304 chr8:9761905 MIR124-1;LOC157627 additive 0.0000123 -0.0088454
8p23.1 Mean cg06545268 chr8:9756974 additive 0.0000150 0.0110763
8p23.1 Mean cg18452600 chr8:9911543 MSRA dominant 0.0000034 0.0152856
8p23.1 Mean cg10220992 chr8:11324327 FAM167A additive 0.0000229 0.0079994
8p23.1 Mean cg02621357 chr8:11296980 FAM167A additive 0.0000260 0.0059709
8p23.1 Mean cg19403029 chr8:10587055 SOX7 additive 0.0000278 -0.0074851
8p23.1 Mean cg25447652 chr8:11205754 TDH additive 0.0000300 -0.0105272
8p23.1 Mean cg26670620 chr8:12244544 FAM66A dominant 0.0000014 0.0327622
8p23.1 Mean cg23565027 chr8:11021173 XKR6 additive 0.0000406 0.0082572
8p23.1 Mean cg01644798 chr8:11617305 GATA4 additive 0.0000412 -0.0064120
8p23.1 Mean cg02326058 chr8:8993102 additive 0.0000478 -0.0082233
8p23.1 Mean cg21880079 chr8:8419587 additive 0.0000495 0.0043253
8p23.1 Mean cg07890238 chr8:8182454 PRAGMIN recessive 0.0000093 0.0139184
8p23.1 Mean cg01706263 chr8:10893100 MIR598;XKR6 additive 0.0000535 0.0042901
8p23.1 Mean cg14702231 chr8:11413234 BLK additive 0.0000603 0.0066302
8p23.1 Mean cg03024720 chr8:9765601 additive 0.0001131 -0.0050975
8p23.1 Mean cg02227026 chr8:8173791 recessive 0.0000268 0.0074965
8p23.1 Mean cg02101571 chr8:11853878 DEFB134 additive 0.0001419 0.0063608
8p23.1 Mean cg22917652 chr8:10283152 MSRA additive 0.0001516 0.0049731
8p23.1 Mean cg26621943 chr8:10275927 MSRA additive 0.0001524 -0.0050858
8p23.1 Mean cg04413673 chr8:10470278 RP1L1 additive 0.0001642 0.0069783
8p23.1 Mean cg19996406 chr8:8318774 additive 0.0001786 -0.0072372
8p23.1 Mean cg07353006 chr8:10405104 dominant 0.0000243 0.0135126
8p23.1 Mean cg10147394 chr8:11350297 BLK additive 0.0002023 0.0054931
8p23.1 Mean cg26794885 chr8:12908302 additive 0.0002228 -0.0109642
8p23.1 Mean cg07229212 chr8:11056726 XKR6 additive 0.0002275 -0.0084718
8p23.1 Mean cg03790427 chr8:10530123 C8orf74 additive 0.0002275 0.0052998
8p23.1 Mean cg07756338 chr8:11882897 additive 0.0002343 0.0054734
8p23.1 Mean cg07668586 chr8:11772215 additive 0.0002371 0.0050502
8p23.1 Mean cg04057858 chr8:10383763 T-SP1 additive 0.0002638 0.0032578
8p23.1 Mean cg27515052 chr8:8513104 additive 0.0002744 -0.0065508
8p23.1 Mean cg26550646 chr8:8175407 PRAGMIN dominant 0.0001696 0.0057128
8p23.1 Mean cg01619129 chr8:10697017 PINX1 additive 0.0003417 -0.0037303
8p23.1 Mean cg08833675 chr8:10586790 SOX7 additive 0.0003739 -0.0062212
8p23.1 Mean cg26598540 chr8:10753147 additive 0.0004021 0.0095145
8p23.1 Mean cg24386894 chr8:8863572 ERI1 additive 0.0004081 -0.0045402
8p23.1 Mean cg23730558 chr8:10865623 XKR6 additive 0.0004602 0.0052076
8p23.1 Mean cg25377605 chr8:10513717 RP1L1 additive 0.0004708 0.0051469
8p23.1 Mean cg03899229 chr8:8821258 dominant 0.0000115 -0.0126452
8p23.1 Mean cg10543574 chr8:9763159 additive 0.0004774 0.0058940
8p23.1 Mean cg27378814 chr8:12941186 DLC1 additive 0.0004919 -0.0105938
8p23.1 Mean cg11598005 chr8:11665962 FDFT1 additive 0.0006336 -0.0052335
8p23.1 Mean cg03145322 chr8:10386846 T-SP1 additive 0.0006669 0.0067093
8p23.1 Mean cg00115954 chr8:11536551 additive 0.0006717 -0.0037598
8p23.1 Mean cg11040268 chr8:10447472 additive 0.0007010 -0.0055663
8p23.1 Mean cg07042170 chr8:8831422 dominant 0.0003914 -0.0123087
8p23.1 Mean cg01072821 chr8:10382165 T-SP1 recessive 0.0001000 -0.0106216
8p23.1 Mean cg15893108 chr8:7113417 FAM90A13;FAM90A14 recessive 0.0000462 -0.0176880
8p23.1 Mean cg12810313 chr8:10192475 MSRA additive 0.0009698 0.0050068
8p23.1 Mean cg08711378 chr8:11471054 recessive 0.0001865 0.0144154
8p23.1 Mean cg20633203 chr8:8239143 PRAGMIN additive 0.0011177 0.0044552
8p23.1 Mean cg09300171 chr8:7434722 FAM90A7 additive 0.0015358 0.0037953
8p23.1 Mean cg09817024 chr8:11471395 additive 0.0015621 0.0149230
8p23.1 Mean cg19172575 chr8:11567721 GATA4 additive 0.0015755 -0.0030256
8p23.1 Mean cg06940756 chr8:10927738 XKR6 dominant 0.0011947 -0.0058283
8p23.1 Mean cg14764956 chr8:8239338 PRAGMIN additive 0.0019238 0.0048690
8p23.1 Mean cg10809491 chr8:11204833 TDH additive 0.0019357 0.0051419
8p23.1 Mean cg20905180 chr8:11149412 MTMR9 dominant 0.0003914 0.0143081
8p23.1 Mean cg02457461 chr8:9913680 MSRA additive 0.0020415 0.0061514
8p23.1 Mean cg08596486 chr8:12938311 additive 0.0020849 -0.0054848
8p23.1 Mean cg24899626 chr8:10512724 RP1L1 additive 0.0022892 0.0047481
8p23.1 Mean cg24338833 chr8:10592227 additive 0.0023027 0.0044411
8p23.1 Mean cg20213479 chr8:10460029 additive 0.0023204 0.0036499
8p23.1 Mean cg12996100 chr8:11470690 additive 0.0023394 0.0063445
8p23.1 Mean cg02109073 chr8:8176460 PRAGMIN dominant 0.0005604 0.0116807
8p23.1 Mean cg16847396 chr8:10489236 RP1L1 recessive 0.0007180 0.0086628
8p23.1 Mean cg10419849 chr8:9537322 TNKS additive 0.0028300 0.0038786
8p23.1 Mean cg10823658 chr8:10919403 XKR6 dominant 0.0025652 0.0059496
8p23.1 Mean cg24415728 chr8:11471816 additive 0.0030840 0.0080598
8p23.1 Mean cg10585806 chr8:9987847 MSRA additive 0.0030908 0.0049167
8p23.1 Mean cg01359236 chr8:11763828 recessive 0.0007056 0.0081301
8p23.1 Mean cg05852732 chr8:11832565 DEFB136 additive 0.0035550 0.0053279
8p23.1 Mean cg27030482 chr8:11539320 additive 0.0037144 0.0060514
8p23.1 Mean cg13519851 chr8:10916560 XKR6 recessive 0.0000434 -0.0126974
8p23.1 Mean cg07301044 chr8:9765583 additive 0.0040475 -0.0057308
8p23.1 Mean cg26788142 chr8:11747049 additive 0.0045068 -0.0031013
8p23.1 Mean cg09052083 chr8:10873619 XKR6 additive 0.0046082 -0.0050120
8p23.1 Mean cg25083091 chr8:10646690 PINX1 dominant 0.0045484 0.0063943
8p23.1 Mean cg02601489 chr8:11203954 TDH additive 0.0050200 0.0090877
8p23.1 Mean cg09974041 chr8:10273890 MSRA additive 0.0050489 -0.0030941
8p23.1 Mean cg11320910 chr8:11538786 additive 0.0052387 0.0020605
8p23.1 Mean cg12981288 chr8:11183844 MTMR9 additive 0.0055238 0.0032818
8p23.1 Mean cg18127003 chr8:11614472 GATA4 additive 0.0055238 -0.0035406
8p23.1 Mean cg07556789 chr8:11538570 additive 0.0055386 0.0021348
8p23.1 Mean cg17526103 chr8:9765691 additive 0.0055820 -0.0065900
8p23.1 Mean cg12807628 chr8:11838843 DEFB135 additive 0.0055820 0.0042255
8p23.1 Mean cg16284953 chr8:11471571 additive 0.0058740 0.0071390
8p23.1 Mean cg04879378 chr8:10929210 XKR6 additive 0.0069301 0.0047191
8p23.1 Mean cg24574147 chr8:10918572 XKR6 additive 0.0070411 0.0039270
8p23.1 Mean cg01131038 chr8:10592118 dominant 0.0054092 0.0090784
8p23.1 Mean cg06952801 chr8:10460235 additive 0.0074275 0.0060125
8p23.1 Mean cg06266132 chr8:11853121 DEFB134 additive 0.0075776 0.0054523
8p23.1 Mean cg05759166 chr8:10452896 additive 0.0085096 0.0049364
8p23.1 Mean cg16782885 chr8:11541421 additive 0.0085233 0.0068567
8p23.1 Mean cg02898412 chr8:11623524 additive 0.0091606 0.0050782
8p23.1 Mean cg25519723 chr8:8402366 additive 0.0094668 0.0029393
8p23.1 Mean cg20819482 chr8:9472057 TNKS additive 0.0095947 -0.0048889
8p23.1 Mean cg11374933 chr8:9766172 additive 0.0101221 0.0045496
8p23.1 Mean cg04218812 chr8:9763263 additive 0.0104174 0.0042666
8p23.1 Mean cg25455865 chr8:8960015 recessive 0.0104721 0.0071077
8p23.1 Mean cg07291889 chr8:11471712 additive 0.0111515 0.0049492
8p23.1 Mean cg07356412 chr8:11044280 XKR6 additive 0.0115780 0.0030463
8p23.1 Mean cg01489256 chr8:11204017 TDH additive 0.0117034 -0.0103298
8p23.1 Mean cg13283153 chr8:9756828 additive 0.0117767 0.0045982
8p23.1 Mean cg23158754 chr8:9766135 additive 0.0118898 -0.0058709
8p23.1 Mean cg06869039 chr8:12838022 C8orf79 additive 0.0133644 -0.0055239
8p23.1 Mean cg04291970 chr8:11226339 C8orf12 additive 0.0146165 0.0039770
8p23.1 Mean cg26339990 chr8:12878608 C8orf79 additive 0.0148870 -0.0047243
8p23.1 Mean cg17155499 chr8:11644644 NEIL2 dominant 0.0016184 0.0071299
8p23.1 Mean cg09031473 chr8:10593133 dominant 0.0120959 0.0051498
8p23.1 Mean cg09500200 chr8:9763033 recessive 0.0110124 -0.0074537
8p23.1 Mean cg08447380 chr8:8185703 PRAGMIN additive 0.0158063 0.0024195
8p23.1 Mean cg08196601 chr8:12869553 C8orf79 recessive 0.0044940 -0.0092654
8p23.1 Mean cg00870242 chr8:10530148 C8orf74 additive 0.0173984 0.0027906
8p23.1 Mean cg17981470 chr8:10470999 RP1L1 additive 0.0178878 0.0040340
8p23.1 Mean cg07935657 chr8:10622805 additive 0.0182818 0.0105775
8p23.1 Mean cg09460231 chr8:10736649 additive 0.0184161 0.0053629
8p23.1 Mean cg27108504 chr8:10123853 MSRA additive 0.0188582 -0.0032791
8p23.1 Mean cg11824826 chr8:9953022 MSRA recessive 0.0059706 0.0057774
8p23.1 Mean cg21919729 chr8:11719367 CTSB dominant 0.0186866 0.0083721
8p23.1 Mean cg02310165 chr8:10892734 XKR6;MIR598 additive 0.0208055 0.0035155
8p23.1 Mean cg03192020 chr8:11204681 TDH dominant 0.0161481 0.0055014
8p23.1 Mean cg17802537 chr8:8857094 additive 0.0212431 -0.0038001
8p23.1 Mean cg26020513 chr8:11568356 GATA4 additive 0.0215001 0.0071033
8p23.1 Mean cg24520755 chr8:9996632 MSRA additive 0.0215100 -0.0036860
8p23.1 Mean cg05362548 chr8:11205166 TDH additive 0.0215100 0.0031058
8p23.1 Mean cg20781335 chr8:10466983 RP1L1 additive 0.0215100 0.0040070
8p23.1 Mean cg08911368 chr8:11471085 additive 0.0215100 0.0091888
8p23.1 Mean cg13440795 chr8:10210267 MSRA dominant 0.0016285 0.0070063
8p23.1 Mean cg21535000 chr8:9760877 LOC157627 dominant 0.0090629 0.0053863
8p23.1 Mean cg07068655 chr8:12633029 LOC340357 dominant 0.0094670 -0.0037314
8p23.1 Mean cg15906055 chr8:11195919 TDH dominant 0.0102963 -0.0047886
8p23.1 Mean cg04657224 chr8:11059038 XKR6 dominant 0.0108584 0.0035216
8p23.1 Mean cg25191598 chr8:12809941 C8orf79 dominant 0.0139446 0.0063202
8p23.1 Mean cg04345694 chr8:8439596 dominant 0.0209244 0.0046635
8p23.1 Mean cg18420643 chr8:10590503 recessive 0.0017669 0.0071280
8p23.1 Mean cg13434842 chr8:11567896 GATA4 recessive 0.0045562 -0.0082657
8p23.1 Mean cg02935780 chr8:12788931 recessive 0.0098587 -0.0104883
8p23.1 Mean cg23282442 chr8:11225832 C8orf12;TDH recessive 0.0117378 0.0072181
8p23.1 Mean cg27044841 chr8:8580960 recessive 0.0173661 -0.0124387
8p23.1 Mean cg22883125 chr8:11540758 recessive 0.0189570 0.0098727
8p23.1 Mean cg04015433 chr8:8820844 recessive 0.0195630 0.0111140
8p23.1 Mean cg27100760 chr8:10708248 recessive 0.0209381 -0.0083211
Enrichment analysis results for mean differentially methylated (MDM) genes in inversion 8p23.1 using GO database.

Figure 12: Enrichment analysis results for mean differentially methylated (MDM) genes in inversion 8p23.1 using GO database

Inversion 16p11.2

The CpG sites that appear in Table 7 are DMD according to the 16p11.2 region status. Moreover, the enrichment of the genes that contain these CpG sites is presented in Figure 13.


Table 7: Significant mean differentially methylated CpG sites according to inversion 16p11.2 genotype
Inversion Type_analysis CpG Location Gene_Symbol model adj.p.value DiffLevene_logFC
16p11.2 Mean cg09046979 chr16:28333134 SBK1 additive 0.0000000 -0.0590529
16p11.2 Mean cg04270652 chr16:28608894 SULT1A2 additive 0.0000000 -0.0301901
16p11.2 Mean cg27413008 chr16:28519597 IL27 additive 0.0000000 -0.0345394
16p11.2 Mean cg26624097 chr16:28620651 SULT1A1 additive 0.0000000 0.0426758
16p11.2 Mean cg01542023 chr16:28550637 NUPR1 additive 0.0000000 -0.0218598
16p11.2 Mean cg02896250 chr16:28305533 SBK1 additive 0.0000000 -0.0147799
16p11.2 Mean cg17122311 chr16:28517278 IL27 additive 0.0000000 -0.0115008
16p11.2 Mean cg05683445 chr16:28303182 SBK1 additive 0.0000000 0.0138940
16p11.2 Mean cg00348858 chr16:28858442 TUFM additive 0.0000000 -0.0161799
16p11.2 Mean cg03300649 chr16:28504949 APOB48R;CLN3 additive 0.0000000 -0.0112055
16p11.2 Mean cg01378222 chr16:28622494 SULT1A1 additive 0.0000000 0.0201353
16p11.2 Mean cg00201760 chr16:28518385 IL27 additive 0.0000000 -0.0066276
16p11.2 Mean cg26792089 chr16:28518200 IL27 additive 0.0000000 -0.0086291
16p11.2 Mean cg01621080 chr16:28608125 SULT1A2 additive 0.0000000 -0.0191912
16p11.2 Mean cg09754948 chr16:28834200 ATXN2L additive 0.0000000 0.0207868
16p11.2 Mean cg08761264 chr16:28874980 SH2B1 additive 0.0000000 -0.0146328
16p11.2 Mean cg26603685 chr16:28620355 SULT1A1 additive 0.0000000 0.0141158
16p11.2 Mean cg02195680 chr16:28519566 IL27 additive 0.0000000 -0.0083101
16p11.2 Mean cg06726893 chr16:28870846 additive 0.0000000 -0.0128628
16p11.2 Mean cg06288570 chr16:28550567 NUPR1 additive 0.0000000 0.0075608
16p11.2 Mean cg08180572 chr16:28985143 SPNS1 additive 0.0000000 -0.0213145
16p11.2 Mean cg27016020 chr16:28303432 SBK1 additive 0.0000000 0.0105083
16p11.2 Mean cg10436792 chr16:28889110 ATP2A1 additive 0.0000000 -0.0134999
16p11.2 Mean cg07884168 chr16:28874307 SH2B1 additive 0.0000018 -0.0189530
16p11.2 Mean cg04413090 chr16:28302913 SBK1 additive 0.0000018 0.0083194
16p11.2 Mean cg05590982 chr16:28550171 NUPR1 additive 0.0000039 0.0083566
16p11.2 Mean cg00272903 chr16:28300253 additive 0.0000089 0.0096998
16p11.2 Mean cg00536289 chr16:28834130 ATXN2L dominant 0.0000037 -0.0064095
16p11.2 Mean cg04244056 chr16:28835698 ATXN2L additive 0.0000218 0.0063856
16p11.2 Mean cg26489497 chr16:28512017 IL27 additive 0.0000324 0.0042995
16p11.2 Mean cg00489954 chr16:28855387 TUFM dominant 0.0000451 0.0061871
16p11.2 Mean cg27473355 chr16:28915234 ATP2A1 additive 0.0000834 0.0040903
16p11.2 Mean cg08213689 chr16:28893874 ATP2A1 additive 0.0001154 0.0076508
16p11.2 Mean cg01161644 chr16:28270238 additive 0.0001154 -0.0082059
16p11.2 Mean cg25341726 chr16:28518331 IL27 additive 0.0001685 -0.0052976
16p11.2 Mean cg26663590 chr16:28959310 additive 0.0002295 0.0058851
16p11.2 Mean cg00204512 chr16:28754710 dominant 0.0000326 -0.0060013
16p11.2 Mean cg08726667 chr16:28573379 CCDC101 additive 0.0004551 0.0053023
16p11.2 Mean cg02329193 chr16:29196472 additive 0.0011103 -0.0044675
16p11.2 Mean cg04609801 chr16:28609176 SULT1A2 additive 0.0024163 -0.0061258
16p11.2 Mean cg26872100 chr16:28270754 additive 0.0067904 -0.0050429
16p11.2 Mean cg26701545 chr16:28331026 SBK1 dominant 0.0073350 -0.0071532
16p11.2 Mean cg16576597 chr16:28551801 NUPR1 additive 0.0085387 0.0043544
16p11.2 Mean cg06723057 chr16:28549923 NUPR1 additive 0.0112408 0.0025291
16p11.2 Mean cg06897606 chr16:28270673 additive 0.0122980 -0.0059785
16p11.2 Mean cg02358434 chr16:28995271 SPNS1;LAT dominant 0.0126779 0.0044088
16p11.2 Mean cg04761177 chr16:28898644 ATP2A1 dominant 0.0149695 -0.0050702
16p11.2 Mean cg05280508 chr16:28486629 dominant 0.0081569 -0.0067688
16p11.2 Mean cg11094938 chr16:28888844 ATP2A1 additive 0.0213980 -0.0026259
16p11.2 Mean cg12743398 chr16:28609531 SULT1A2 dominant 0.0022667 0.0187413
Enrichment analysis results for mean differentially methylated (MDM) genes in inversion 16p11.2. A) Results for the enrichment using DisGeNET database; B) Enrichment results using GO.

Figure 13: Enrichment analysis results for mean differentially methylated (MDM) genes in inversion 16p11.2
A) Results for the enrichment using DisGeNET database; B) Enrichment results using GO.

Inversion 17q21.31

Table 8 displays the CpG sites DMD depending on the inversion 17q21.31 genotype. Their respective genes have been used for an enrichment analysis which results are shown in Figure 14.


Table 8: Significant mean differentially methylated CpG sites according to inversion 17q21.31 genotype
Inversion Type_analysis CpG Location Gene_Symbol model adj.p.value DiffLevene_logFC
17q21.31 Mean cg05159804 chr17:44343776 additive 0.0000000 -0.1129002
17q21.31 Mean cg22968622 chr17:43663579 dominant 0.0000000 0.4881827
17q21.31 Mean cg12609785 chr17:43660871 additive 0.0000000 0.2598851
17q21.31 Mean cg19832721 chr17:44249866 KIAA1267 additive 0.0000000 0.1195135
17q21.31 Mean cg08113562 chr17:43508428 SH3D20 additive 0.0000000 0.1300643
17q21.31 Mean cg09764761 chr17:44105544 MAPT additive 0.0000000 -0.0517372
17q21.31 Mean cg07368061 chr17:44090862 MAPT additive 0.0000000 -0.0466625
17q21.31 Mean cg01341218 chr17:43662625 additive 0.0000000 0.0410505
17q21.31 Mean cg01882395 chr17:43717810 C17orf69 additive 0.0000000 0.0346404
17q21.31 Mean cg03954353 chr17:43715162 C17orf69;MGC57346 additive 0.0000000 0.0315196
17q21.31 Mean cg00891649 chr17:43972573 MAPT;LOC100130148;LOC100128977 additive 0.0000000 -0.0343202
17q21.31 Mean cg14374015 chr17:44249569 KIAA1267 additive 0.0000000 0.0338557
17q21.31 Mean cg22433210 chr17:43662623 additive 0.0000000 0.0315742
17q21.31 Mean cg23659289 chr17:43472725 ARHGAP27 additive 0.0000000 0.0164382
17q21.31 Mean cg05301556 chr17:43971177 MAPT;LOC100128977 additive 0.0000000 -0.0270672
17q21.31 Mean cg27503360 chr17:43890749 CRHR1 additive 0.0000000 -0.0162679
17q21.31 Mean cg21214508 chr17:44248233 KIAA1267 additive 0.0000000 -0.0322238
17q21.31 Mean cg05772917 chr17:44027251 MAPT additive 0.0000000 0.0171359
17q21.31 Mean cg04491389 chr17:44214771 KIAA1267 additive 0.0000000 -0.0305095
17q21.31 Mean cg13732302 chr17:44222207 KIAA1267 additive 0.0000000 -0.0279081
17q21.31 Mean cg08670715 chr17:44341754 dominant 0.0000000 0.0370365
17q21.31 Mean cg23616531 chr17:44269258 additive 0.0000000 -0.0339657
17q21.31 Mean cg01934064 chr17:44064242 MAPT additive 0.0000000 0.0234691
17q21.31 Mean cg07368127 chr17:44230994 KIAA1267 additive 0.0000000 0.0318063
17q21.31 Mean cg05186793 chr17:44235520 KIAA1267 additive 0.0000000 0.0344788
17q21.31 Mean cg23952828 chr17:44246087 KIAA1267 additive 0.0000000 0.0154349
17q21.31 Mean cg18410271 chr17:43472435 ARHGAP27 additive 0.0000000 0.0074472
17q21.31 Mean cg26855231 chr17:44249543 KIAA1267 additive 0.0000000 0.0226924
17q21.31 Mean cg07067577 chr17:43506829 SH3D20 additive 0.0000000 -0.0113738
17q21.31 Mean cg24063856 chr17:43863303 CRHR1 additive 0.0000000 -0.0260940
17q21.31 Mean cg19943578 chr17:43483527 ARHGAP27 additive 0.0000000 -0.0113516
17q21.31 Mean cg00480298 chr17:44068857 MAPT additive 0.0000000 0.0230431
17q21.31 Mean cg02301815 chr17:44249491 KIAA1267 additive 0.0000000 -0.0204581
17q21.31 Mean cg12798194 chr17:43462791 additive 0.0000000 0.0187522
17q21.31 Mean cg24203758 chr17:43507018 SH3D20 additive 0.0000000 -0.0229969
17q21.31 Mean cg13947929 chr17:43863356 CRHR1 additive 0.0000000 -0.0116069
17q21.31 Mean cg22128613 chr17:44061117 MAPT additive 0.0000000 0.0170594
17q21.31 Mean cg12604352 chr17:44073915 MAPT additive 0.0000000 -0.0229072
17q21.31 Mean cg10955972 chr17:43976002 MAPT;LOC100130148 additive 0.0000000 0.0103646
17q21.31 Mean cg17554502 chr17:44271559 additive 0.0000000 0.0168114
17q21.31 Mean cg10224600 chr17:43975063 MAPT;LOC100130148 additive 0.0000000 0.0197249
17q21.31 Mean cg26250449 chr17:44195907 KIAA1267 additive 0.0000000 -0.0200634
17q21.31 Mean cg16642545 chr17:43878769 CRHR1 additive 0.0000000 -0.0120099
17q21.31 Mean cg07584200 chr17:44185029 KIAA1267 additive 0.0000000 0.0142890
17q21.31 Mean cg27551605 chr17:43862910 CRHR1 additive 0.0000000 -0.0116885
17q21.31 Mean cg06491244 chr17:44851046 WNT3 additive 0.0000000 0.0056960
17q21.31 Mean cg00715050 chr17:43472920 ARHGAP27 additive 0.0000000 0.0079899
17q21.31 Mean cg14260695 chr17:43506184 additive 0.0000000 -0.0132760
17q21.31 Mean cg08358943 chr17:44889584 WNT3 additive 0.0000000 0.0114873
17q21.31 Mean cg19872068 chr17:44250734 KIAA1267 additive 0.0000000 -0.0097687
17q21.31 Mean cg05251861 chr17:43503394 ARHGAP27 additive 0.0000000 -0.0154974
17q21.31 Mean cg18119429 chr17:44270215 additive 0.0000000 0.0130878
17q21.31 Mean cg01640727 chr17:44029468 MAPT dominant 0.0000000 -0.0186422
17q21.31 Mean cg00025823 chr17:43909151 CRHR1 additive 0.0000000 0.0108103
17q21.31 Mean cg02665463 chr17:44657154 ARL17A additive 0.0000001 0.0515584
17q21.31 Mean cg13465858 chr17:44204908 KIAA1267 additive 0.0000001 -0.0151230
17q21.31 Mean cg00677574 chr17:43221327 ACBD4 additive 0.0000001 -0.0285180
17q21.31 Mean cg06100756 chr17:43221575 dominant 0.0000002 -0.0272045
17q21.31 Mean cg00348467 chr17:43222121 dominant 0.0000001 -0.0153352
17q21.31 Mean cg07778819 chr17:43862927 CRHR1 dominant 0.0000001 -0.0129000
17q21.31 Mean cg00625783 chr17:43222106 additive 0.0000012 -0.0098780
17q21.31 Mean cg17372941 chr17:43222115 dominant 0.0000010 -0.0100327
17q21.31 Mean cg17178468 chr17:43049442 additive 0.0000045 0.0049710
17q21.31 Mean cg27395066 chr17:43221220 ACBD4 additive 0.0000045 -0.0288361
17q21.31 Mean cg02932314 chr17:42733698 C17orf104 additive 0.0000070 -0.0145782
17q21.31 Mean cg15072306 chr17:43922875 LOC100128977;IMP5 additive 0.0000080 -0.0064886
17q21.31 Mean cg15156975 chr17:43449055 additive 0.0000129 -0.0120818
17q21.31 Mean cg06471905 chr17:42835688 ADAM11 additive 0.0000151 0.0037251
17q21.31 Mean cg12127472 chr17:42733724 C17orf104 additive 0.0000231 -0.0172817
17q21.31 Mean cg06649191 chr17:42908211 GJC1 additive 0.0000372 0.0095219
17q21.31 Mean cg00022871 chr17:43884358 CRHR1 additive 0.0001391 -0.0049349
17q21.31 Mean cg16573346 chr17:44020278 MAPT additive 0.0001450 0.0094528
17q21.31 Mean cg10701640 chr17:43249399 additive 0.0002350 -0.0175842
17q21.31 Mean cg04976685 chr17:43449285 additive 0.0003154 -0.0100207
17q21.31 Mean cg15639951 chr17:43367609 MAP3K14 additive 0.0003257 -0.0042282
17q21.31 Mean cg06729642 chr17:43324793 LOC100133991 dominant 0.0002123 -0.0095029
17q21.31 Mean cg08929103 chr17:43860355 CRHR1 additive 0.0003648 -0.0046606
17q21.31 Mean cg09581049 chr17:42998320 additive 0.0003739 0.0052022
17q21.31 Mean cg13215995 chr17:43222258 additive 0.0005163 -0.0049477
17q21.31 Mean cg25105522 chr17:43355089 MAP3K14 additive 0.0005636 0.0122137
17q21.31 Mean cg24180402 chr17:43221464 ACBD4 additive 0.0005851 -0.0110929
17q21.31 Mean cg08496953 chr17:42733527 C17orf104 additive 0.0007656 -0.0160496
17q21.31 Mean cg13550419 chr17:44898510 additive 0.0009796 -0.0049300
17q21.31 Mean cg04382470 chr17:43974975 MAPT;LOC100130148 additive 0.0011534 0.0072692
17q21.31 Mean cg07993743 chr17:44928288 WNT9B additive 0.0012075 -0.0087875
17q21.31 Mean cg04992638 chr17:43339328 C17orf46;LOC100133991 additive 0.0012153 0.0040613
17q21.31 Mean cg11969213 chr17:43324322 LOC100133991;FMNL1 additive 0.0015940 -0.0064094
17q21.31 Mean cg19407385 chr17:43099144 dominant 0.0010953 0.0261416
17q21.31 Mean cg24349819 chr17:43476547 ARHGAP27 dominant 0.0011522 0.0047931
17q21.31 Mean cg03785666 chr17:43324416 LOC100133991;FMNL1 additive 0.0017830 -0.0060942
17q21.31 Mean cg03209459 chr17:44604660 ARL17A;LRRC37A2 additive 0.0019379 -0.0108676
17q21.31 Mean cg09250749 chr17:44271316 additive 0.0021367 0.0074298
17q21.31 Mean cg20840174 chr17:44087784 MAPT additive 0.0023942 -0.0037086
17q21.31 Mean cg15690475 chr17:44101453 MAPT dominant 0.0006506 -0.0058092
17q21.31 Mean cg24394631 chr17:43863000 CRHR1 additive 0.0029465 -0.0080932
17q21.31 Mean cg23907852 chr17:43922244 LOC100128977;IMP5 additive 0.0032991 0.0028090
17q21.31 Mean cg10598582 chr17:43093761 additive 0.0047092 0.0051398
17q21.31 Mean cg12286573 chr17:42734503 C17orf104 additive 0.0047092 0.0092711
17q21.31 Mean cg24677220 chr17:44075684 MAPT;STH dominant 0.0014669 0.0067886
17q21.31 Mean cg27457921 chr17:43976811 MAPT dominant 0.0020022 0.0073739
17q21.31 Mean cg21095561 chr17:42733994 C17orf104 dominant 0.0047407 -0.0100535
17q21.31 Mean cg12633764 chr17:43978756 MAPT additive 0.0058811 0.0034843
17q21.31 Mean cg10256219 chr17:44270511 additive 0.0069141 0.0074597
17q21.31 Mean cg01440864 chr17:44892087 WNT3 additive 0.0086836 0.0058238
17q21.31 Mean cg19539667 chr17:43339831 LOC100133991;C17orf46 additive 0.0090486 -0.0036384
17q21.31 Mean cg03706109 chr17:43090472 additive 0.0092657 0.0048153
17q21.31 Mean cg16734549 chr17:43488551 ARHGAP27 dominant 0.0044139 0.0044700
17q21.31 Mean cg19156875 chr17:43974446 MAPT;LOC100130148 recessive 0.0107245 0.0168792
17q21.31 Mean cg03723148 chr17:43921863 LOC100128977;IMP5 recessive 0.0029048 -0.0082081
17q21.31 Mean cg14633020 chr17:43194301 PLCD3 additive 0.0120489 0.0049921
17q21.31 Mean cg25560772 chr17:45057470 RPRML dominant 0.0071130 -0.0116417
17q21.31 Mean cg20769177 chr17:44928516 WNT9B additive 0.0127040 -0.0178243
17q21.31 Mean cg16772514 chr17:43046872 C1QL1 additive 0.0135717 0.0020695
17q21.31 Mean cg26226202 chr17:44928552 WNT9B additive 0.0140419 -0.0098593
17q21.31 Mean cg17881353 chr17:44928210 WNT9B dominant 0.0108268 -0.0157611
17q21.31 Mean cg18050844 chr17:44909987 additive 0.0208820 0.0056215
17q21.31 Mean cg12393668 chr17:42768503 CCDC43 dominant 0.0212097 -0.0066238
17q21.31 Mean cg19563671 chr17:43224158 HEXIM1 dominant 0.0042189 0.0229999
17q21.31 Mean cg24042242 chr17:43044660 C1QL1 dominant 0.0071874 -0.0128387
17q21.31 Mean cg08301612 chr17:43228571 HEXIM1 dominant 0.0130497 -0.0076557
17q21.31 Mean cg14630905 chr17:44928992 WNT9B recessive 0.0074608 0.0159778
17q21.31 Mean cg04102519 chr17:44843875 WNT3 recessive 0.0122555 0.0152973
17q21.31 Mean cg12297030 chr17:43662878 recessive 0.0188742 0.0115852
Enrichment analysis results for mean differentially methylated (MDM) genes in inversion 17q21.31. A) Enrichment results using KEGG; B) Results for the enrichment using GO database.

Figure 14: Enrichment analysis results for mean differentially methylated (MDM) genes in inversion 17q21.31
A) Enrichment results using KEGG; B) Results for the enrichment using GO database.

2.1.3 MDA metabolome

Table 9 shows the only metabolite differentially concentrated according to the inversion 8p23.1 genotype.


Table 9: Significant mean differentially concentrated metabolites for inversion 8p23.1.
Metabolome Inversion Type_analysis Metabolite model adj.P.Val DiffLevene_logFC
Urine 8p23.1 Mean Sucrose additive 0.0199054 0.2819581
Urine 8p23.1 Mean Sucrose dominant 0.0131570 0.4482716

2.1.4 MDA for transcriptome using inversion*exposome interaction

The results of the differential analysis according to the genotype*exposure are displayed in Table 10 and Figure 15 for inverison 8p23.1, Table 11 and Figure 17 for inversion 16p11.2, and Table 12 and Figures 18 and 19 for inversion 17q21.31. The only enrichment analysis that has revealed results is the one that has used MDE genes for inversion 8p23.1 (Figure 16).

Inversion 8p23.1


Table 10: Significant mean differentially expressed genes according to inversion 8p23.1 genotype*exposome interaction
Exposure Exposure_abrev Family Inversion Type_analysis Transcript Location Gene_Symbol adj.p.value DiffLevene_logFC
h_ln_cat_preg_None Traffic noise (night) Noise 8p23.1 Mean TC08000963.hg.1 chr8:10713595-10716946 AK094525 0.0457837 0.0739552
h_ln_cat_preg_None Traffic noise (night) Noise 8p23.1 Mean TC08000949.hg.1 chr8:9144982-9145088 RNU6-1151P;U6 0.0457837 -0.1240038
h_pressure_t1_None Pressure (t1) Meteorological 8p23.1 Mean TC08000919.hg.1 chr8:7272382-7274385 DEFB4B 0.0318741 0.0035486
hs_bpa_madj_Log2 BPA Phenols 8p23.1 Mean TC08000077.hg.1 chr8:10383056-10411676 PRSS55 0.0315433 0.0171205
hs_pbde47_madj_Log2 PBDE 47 PBDEs 8p23.1 Mean TC08002212.hg.1 chr8:9757531-9762876 LINC00599 0.0297172 -0.0132029
Plot representations for the mean differentially expressed genes when inversion 8p23.1 interacts with exposome. There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Figure 15: Plot representations for the mean differentially expressed genes when inversion 8p23.1 interacts with exposome
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Enrichment analysis for mean differentially expressed (MDE) genes using genotype-environment interaction for inversion 8p23.1. A) Results for the enrichment using KEGG database; B) GO enrichment results.

Figure 16: Enrichment analysis for mean differentially expressed (MDE) genes using genotype-environment interaction for inversion 8p23.1
A) Results for the enrichment using KEGG database; B) GO enrichment results.

Inversion 16p11.2


Table 11: Significant mean differentially expressed genes according to inversion 16p11.2 genotype*exposome interaction
Exposure Exposure_abrev Family Inversion Type_analysis Transcript Location Gene_Symbol adj.p.value DiffLevene_logFC
h_landuseshan300_preg_None Land use (300m) Building Environment 16p11.2 Mean TC16000986.hg.1 chr16:28390900-28437775 EIF3CL;EIF3C 0.0456787 -0.5201213
h_landuseshan300_preg_None Land use (300m) Building Environment 16p11.2 Mean TC16000305.hg.1 chr16:28699879-28747053 EIF3C;EIF3CL 0.0456787 -0.5307593
hs_as_m_Log2 Arsenic Metals 16p11.2 Mean TC16000323.hg.1 chr16:29495626-29495781 DQ576952 0.0231242 0.0295406
hs_cotinine_mcat_None Cotinine Tobacco Smoke 16p11.2 Mean TC16000982.hg.1 chr16:28009616-28009722 RNU6-1241P 0.0027473 0.2001604
hs_globalsmok_m_None Maternal smoking (active and ETS) Tobacco Smoke 16p11.2 Mean TC16000982.hg.1 chr16:28009616-28009722 RNU6-1241P 0.0336587 0.1454652
Plot representations for the mean differentially expressed genes when inversion 16p11.2 interacts with exposome. There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Figure 17: Plot representations for the mean differentially expressed genes when inversion 16p11.2 interacts with exposome
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Inversion 17q21.31


Table 12: Significant mean differentially expressed genes according to inversion 17q21.31 genotype*exposome interaction
Exposure Exposure_abrev Family Inversion Type_analysis Transcript Location Gene_Symbol adj.p.value DiffLevene_logFC
hs_dmp_madj_Log2 DMP OP Pesticides 17q21.31 Mean TC17001591.hg.1 chr17:43100706-43138473 DCAKD 0.0487945 -0.0272306
hs_mnbp_madj_Log2 MnBP Phthalates 17q21.31 Mean TC17001588.hg.1 chr17:42982993-42992920 GFAP;AK124465 0.0097880 0.0127936
hs_zn_m_Log2 Zn Essential minerals 17q21.31 Mean TC17000598.hg.1 chr17:44450179-44500463 NSFP1 0.0230469 0.4424501
hs_zn_m_Log2 Zn Essential minerals 17q21.31 Mean TC17001612.hg.1 chr17:44363862-44439163 ARL17A;ARL17B 0.0230469 0.1752245
hs_zn_m_Log2 Zn Essential minerals 17q21.31 Mean TC17000600.hg.1 chr17:44668035-44834830 NSF;NSFP1 0.0230469 0.2429936
hs_zn_m_Log2 Zn Essential minerals 17q21.31 Mean TC17001613.hg.1 chr17:44594068-44657088 ARL17A 0.0230469 0.1793518
hs_zn_m_Log2 Zn Essential minerals 17q21.31 Mean TC17001618.hg.1 chr17:45110626-45137515 ARL17 0.0230469 0.1908013
Plot representations for the mean differentially expressed genes when inversion 17q21.31 interacts with exposome (1). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Figure 18: Plot representations for the mean differentially expressed genes when inversion 17q21.31 interacts with exposome (1)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Plot representations for the mean differentially expressed genes when inversion 17q21.31 interacts with exposome (2). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Figure 19: Plot representations for the mean differentially expressed genes when inversion 17q21.31 interacts with exposome (2)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

2.1.5 MDA for methylome using inversion*exposome interaction

The differential analysis for methylome using the interaction between the inversion at 8p23.1 and exposome has revelaed the different mean methylation of the CpG sites that are displayed in Table 13. The enrichment results of the genes that contain these CpG sites are illustrated in Figure 20.The same has been implemented for inversion 16p11.2 and inversion 17q21.31 and the results are shown in Table 14 and Figure 21, and Table 15 and Figure 22, respectively.

Inversion 8p23.1


Table 13: Significant mean differentially methylated CpG sites according to inversion 8p23.1 genotype*exposome interaction
Exposure Exposure_abrev Family Inversion Type_analysis CpG Location Gene_Symbol adj.p.value DiffLevene_logFC
1 e3_alcpreg_yn_None Alcohol intake Lifestyle 8p23.1 Mean cg12792075 chr8:12244565 FAM66A 0.0053170 -0.0656532
2 e3_alcpreg_yn_None Alcohol intake Lifestyle 8p23.1 Mean cg26670620 chr8:12244544 FAM66A 0.0269268 -0.0451624
12 h_builtdens300_preg_Sqrt Building density (300m) Building Environment 8p23.1 Mean cg02527252 chr8:8178889 PRAGMIN 0.0444839 0.0000577
17 h_folic_t1_None Folic acid supplementation Lifestyle 8p23.1 Mean cg05753693 chr8:10192930 MSRA;MSRA;MSRA 0.0098659 0.0124488
18 h_folic_t1_None Folic acid supplementation Lifestyle 8p23.1 Mean cg05267444 chr8:11627012 NEIL2;NEIL2;NEIL2;NEIL2 0.0283530 0.0149812
20 h_fruit_preg_Ter Fruits intake Lifestyle 8p23.1 Mean cg26670620 chr8:12244544 FAM66A 0.0105750 -0.0545383
21 h_fruit_preg_Ter Fruits intake Lifestyle 8p23.1 Mean cg12792075 chr8:12244565 FAM66A 0.0105750 -0.0696423
28 h_no2_ratio_preg_Log NO2 (preg) Air Pollution 8p23.1 Mean cg10613815 chr8:11283299 C8orf12;FAM167A 0.0195207 -0.0743761
42 hs_k_m_Log2 K Essential minerals 8p23.1 Mean cg06991484 chr8:11540407 0.0388471 -0.0738248
46 hs_mehhp_madj_Log2 MEHHP Phthalates 8p23.1 Mean cg25925578 chr8:8388047 0.0379205 -0.0059698
50 hs_mn_m_Log2 Manganese Metals 8p23.1 Mean cg14033944 chr8:11627058 NEIL2;NEIL2;NEIL2;NEIL2 0.0250874 -0.0190271
65 hs_pcb118_madj_Log2 PCB 118 OCs 8p23.1 Mean cg11557530 chr8:9911760 MSRA;MSRA 0.0001973 -0.0104222
71 hs_pfhxs_m_Log2 PFHXS PFASs 8p23.1 Mean cg15537082 chr8:9762300 MIR124-1;LOC157627 0.0000224 -0.0158329
78 hs_pfna_m_Log2 PFNA PFASs 8p23.1 Mean cg12792075 chr8:12244565 FAM66A 0.0414350 -0.0446670
82 hs_pfos_m_Log2 PFOS PFASs 8p23.1 Mean cg12792075 chr8:12244565 FAM66A 0.0180689 -0.0498219
88 hs_prpa_madj_Log2 PRPA Phenols 8p23.1 Mean cg22320962 chr8:11560299 GATA4 0.0033215 0.0058054
92 hs_tl_mdich_None Thallium Metals 8p23.1 Mean cg04815626 chr8:9912509 MSRA;MSRA 0.0000004 -0.0735296
Enrichment analysis for mean differentially methylated (MDM) genes using genotype-environment interaction for inversion 8p23.1. A) Results for the enrichment using DisGeNET database; B) GO enrichment results.

Figure 20: Enrichment analysis for mean differentially methylated (MDM) genes using genotype-environment interaction for inversion 8p23.1
A) Results for the enrichment using DisGeNET database; B) GO enrichment results.

Inversion 16p11.2


Table 14: Significant mean differentially methylated CpG sites according to inversion 16p11.2 genotype*exposome interaction
Exposure Exposure_abrev Family Inversion Type_analysis CpG Location Gene_Symbol adj.p.value DiffLevene_logFC
30 h_popdens_preg_Sqrt Population density Building Environment 16p11.2 Mean cg26871973 chr16:28565752 CCDC101 0.0120178 -0.0001515
66 hs_pcb138_madj_Log2 PCB 138 OCs 16p11.2 Mean cg04968132 chr16:27560915 GTF3C1;KIAA0556 0.0140690 0.0079734
67 hs_pcb153_madj_Log2 PCB 153 OCs 16p11.2 Mean cg04968132 chr16:27560915 GTF3C1;KIAA0556 0.0157908 0.0082358
68 hs_pcb170_madj_Log2 PCB 170 OCs 16p11.2 Mean cg07165637 chr16:28102779 0.0399178 -0.0058648
70 hs_pcb180_madj_Log2 PCB 180 OCs 16p11.2 Mean cg04968132 chr16:27560915 GTF3C1;KIAA0556 0.0075376 0.0071593
72 hs_pfhxs_m_Log2 PFHXS PFASs 16p11.2 Mean cg00184016 chr16:28833823 ATXN2L;ATXN2L;ATXN2L;ATXN2L;ATXN2L 0.0000217 -0.0112217
73 hs_pfhxs_m_Log2 PFHXS PFASs 16p11.2 Mean cg09739165 chr16:27637519 KIAA0556 0.0033335 -0.0103411
81 hs_pfoa_m_Log2 PFOA PFASs 16p11.2 Mean cg09629753 chr16:29323721 RUNDC2C 0.0464170 0.0058505
89 hs_prpa_madj_Log2 PRPA Phenols 16p11.2 Mean cg12743398 chr16:28609531 SULT1A2 0.0067656 0.0081282
Enrichment analysis for mean differentially methylated (MDM) genes using genotype-environment interaction for inversion 16p11.2. A) Results for the enrichment using KEGG database; B) Results for the enrichment using DisGeNET database; C) GO enrichment results.

Figure 21: Enrichment analysis for mean differentially methylated (MDM) genes using genotype-environment interaction for inversion 16p11.2
A) Results for the enrichment using KEGG database; B) Results for the enrichment using DisGeNET database; C) GO enrichment results.

Inversion 17q21.31


Table 15: Significant mean differentially methylated CpG sites according to inversion 17q21.31 genotype*exposome interaction
Exposure Exposure_abrev Family Inversion Type_analysis CpG Location Gene_Symbol adj.p.value DiffLevene_logFC
6 h_blueyn300_preg_None Blue spaces (300 m) Natural Spaces 17q21.31 Mean cg11612592 chr17:45266859 CDC27;CDC27 0.0242926 -0.0149990
14 h_fastfood_preg_Ter Fastfood intake Lifestyle 17q21.31 Mean cg03716233 chr17:43128931 DCAKD;DCAKD;DCAKD 0.0025546 0.0168781
26 h_landuseshan300_preg_None Land use (300m) Building Environment 17q21.31 Mean cg13732302 chr17:44222207 KIAA1267 0.0294066 -0.0448199
29 h_pm10_ratio_preg_None PM10 (preg) Air Pollution 17q21.31 Mean cg13001868 chr17:43339223 C17orf46;LOC100133991;LOC100133991 0.0001153 -0.0011285
53 hs_mo_m_Log2 Molybdenum Metals 17q21.31 Mean cg03928887 chr17:43200129 PLCD3 0.0074031 -0.0228002
Enrichment analysis for mean differentially methylated (MDM) genes using genotype-environment interaction for inversion 17q21.31. A) Results for the enrichment using KEGG database; B) GO enrichment results.

Figure 22: Enrichment analysis for mean differentially methylated (MDM) genes using genotype-environment interaction for inversion 17q21.31
A) Results for the enrichment using KEGG database; B) GO enrichment results.

2.2 Inversion - CpG methylation - Gene expression mediation

Table 16 summarizes the mediations of inversion - gene expression by the methylation of CpG sites.


Table 16: Significant mediations between genomic inversions and mean differentially expressed genes mediated by mean differentially methylated CpG sites.
Inversion Transcript Location.Transcript Symbol.Transcript CpG Location.CpG Symbol.CpG p.value.mediation Prop.Mediated p.value.prop.mediated
4 8p23.1 TC08000087.hg.1 chr8:11351510-11422113 BLK cg01383082 chr8:11323474 FAM167A 0.000 0.2064627 0.000
264 8p23.1 TC08000093.hg.1 chr8:11653082-11696818 FDFT1 cg12568669 chr8:11666485 FDFT1 0.000 0.7909002 0.000
270 8p23.1 TC08000093.hg.1 chr8:11653082-11696818 FDFT1 cg12395012 chr8:11607386 GATA4 0.016 0.1526008 0.002
289 8p23.1 TC08000093.hg.1 chr8:11653082-11696818 FDFT1 cg02840367 chr8:11660030 FDFT1 0.001 0.4381081 0.000
363 8p23.1 TC08000093.hg.1 chr8:11653082-11696818 FDFT1 cg24387126 chr8:11617293 GATA4 0.043 0.1297336 0.000
530 8p23.1 TC08000975.hg.1 chr8:11278972-11324276 FAM167A cg01383082 chr8:11323474 FAM167A 0.005 0.1929001 0.000
578 8p23.1 TC08000975.hg.1 chr8:11278972-11324276 FAM167A cg09528494 chr8:11338675 0.000 0.2275709 0.000
2894 8p23.1 TC08000091.hg.1 chr8:11627172-11644855 NEIL2 cg12568669 chr8:11666485 FDFT1 0.000 0.7808629 0.000
2898 8p23.1 TC08000091.hg.1 chr8:11627172-11644855 NEIL2 cg02711665 chr8:11664728 FDFT1 0.008 0.4051327 0.002
2919 8p23.1 TC08000091.hg.1 chr8:11627172-11644855 NEIL2 cg02840367 chr8:11660030 FDFT1 0.005 0.3826641 0.000
5577 16p11.2 TC16000303.hg.1 chr16:28565247-28603111 CCDC101 cg26624097 chr16:28620651 SULT1A1 0.000 0.1470226 0.000
5674 16p11.2 TC16000986.hg.1 chr16:28390900-28437775 EIF3CL;EIF3C cg09046979 chr16:28333134 SBK1 0.007 0.3444712 0.002
5724 16p11.2 TC16000305.hg.1 chr16:28699879-28747053 EIF3C;EIF3CL cg09046979 chr16:28333134 SBK1 0.008 0.3468888 0.004
5727 16p11.2 TC16000305.hg.1 chr16:28699879-28747053 EIF3C;EIF3CL cg26624097 chr16:28620651 SULT1A1 0.037 0.2344032 0.004
5834 16p11.2 TC16000991.hg.1 chr16:28616903-28634907 SULT1A1 cg01378222 chr16:28622494 SULT1A1 0.001 0.9542005 0.000
5840 16p11.2 TC16000991.hg.1 chr16:28616903-28634907 SULT1A1 cg26603685 chr16:28620355 SULT1A1 0.025 0.3621454 0.000
5883 16p11.2 TC16002064.hg.1 chr16:28477974-28503623 CLN3 cg03300649 chr16:28504949 APOB48R;CLN3 0.004 0.4945844 0.000
6040 16p11.2 TC16000990.hg.1 chr16:28603264-28608430 SULT1A2 cg26603685 chr16:28620355 SULT1A1 0.040 0.5651113 0.002
6276 17q21.31 TC17001604.hg.1 chr17:43590734-43593064 AX747150;LRRC37A4P cg12609785 chr17:43660871 0.036 0.7639230 0.022
6277 17q21.31 TC17001604.hg.1 chr17:43590734-43593064 AX747150;LRRC37A4P cg19832721 chr17:44249866 KIAA1267 0.025 0.8168810 0.008

2.3 Impact of the pregnancy exposome on the CpG methylation

The pregnancy exposures that have an impact on mean differentially methylated CpG sites are displayed in Table 17 (p<0.001).


Table 17: Significant associations between pregnancy exposure levels and methylation of individual mean differentially methylated CpG sites.
CpG Location.CpG Symbol.CpG Exposure Exposure.abreviation p.value FDR
195 cg12940923 chr8:10282607 MSRA h_cereal_preg_Ter Cereals intake 0.0000934 0.8191236
282 cg01383082 chr8:11323474 FAM167A h_abs_ratio_preg_Log PMabsorbance (preg) 0.0001804 0.8191236
846 cg02319733 chr8:10282549 MSRA h_cereal_preg_Ter Cereals intake 0.0000304 0.6167447
2164 cg21915799 chr8:10282809 MSRA h_ln_cat_preg_None Traffic noise (night) 0.0009921 0.8191236
2840 cg01601443 chr8:10581988 SOX7 hs_ddt_madj_Log2 DDT 0.0008052 0.8191236
2879 cg01601443 chr8:10581988 SOX7 hs_prpa_madj_Log2 PRPA 0.0003533 0.8191236
3569 cg14257676 chr8:10192642 MSRA h_temperature_t1_None Temperature (t1) 0.0001945 0.8191236
4093 cg12792075 chr8:12244565 FAM66A e3_alcpreg_yn_None Alcohol intake 0.0008227 0.8191236
4897 cg02520399 chr8:8168661 hs_mecpp_madj_Log2 MECPP 0.0005269 0.8191236
4899 cg02520399 chr8:8168661 hs_mehp_madj_Log2 MEHP 0.0001409 0.8191236
4900 cg02520399 chr8:8168661 hs_meohp_madj_Log2 MEOHP 0.0001447 0.8191236
5431 cg06240162 chr8:11142829 MTMR9 h_trafload_preg_pow1over3 Road traffic load (100 m) 0.0005749 0.8191236
5675 cg10039590 chr8:8859974 ERI1 e3_asmokyn_p_None Active smoking (preg) 0.0007744 0.8191236
6119 cg16871763 chr8:11537909 hs_oxbe_madj_Log2 OXBE 0.0006213 0.8191236
7277 cg03059247 chr8:11287657 C8orf12;FAM167A h_lden_cat_preg_None Traffic noise (24h) 0.0008778 0.8191236
7783 cg01048752 chr8:10001523 MSRA hs_meohp_madj_Log2 MEOHP 0.0009975 0.8191236
9810 cg01716419 chr8:11759663 hs_co_m_Log2 Cobalt 0.0004052 0.8191236
9878 cg10613815 chr8:11283299 C8orf12;FAM167A h_greenyn300_preg_None Green spaces (300 m) 0.0003378 0.8191236
12286 cg07890238 chr8:8182454 PRAGMIN h_clf_preg_Log Water Chloroform 0.0002960 0.8191236
12721 cg02227026 chr8:8173791 hs_ohminp_madj_Log2 OH-MiNP 0.0009281 0.8191236
13265 cg07353006 chr8:10405104 hs_k_m_Log2 K 0.0004211 0.8191236
13651 cg03790427 chr8:10530123 C8orf74 hs_ohminp_madj_Log2 OH-MiNP 0.0004012 0.8191236
13949 cg04057858 chr8:10383763 T-SP1 hs_trcs_madj_Log2 TRCS 0.0003413 0.8191236
15271 cg11040268 chr8:10447472 h_fruit_preg_Ter Fruits intake 0.0000232 0.6167447
17220 cg16847396 chr8:10489236 RP1L1 h_fdensity300_preg_Log Facility density (300m) 0.0004619 0.8191236
17223 cg16847396 chr8:10489236 RP1L1 h_frichness300_preg_None Facility richness (300m) 0.0003193 0.8191236
18281 cg09052083 chr8:10873619 XKR6 hs_dmp_madj_Log2 DMP 0.0007223 0.8191236
18375 cg25083091 chr8:10646690 PINX1 hs_dmtp_madj_Log2 DMTP 0.0006649 0.8191236
18854 cg18127003 chr8:11614472 GATA4 hs_mibp_madj_Log2 MiBP 0.0006986 0.8191236
21038 cg04291970 chr8:11226339 C8orf12 h_greenyn300_preg_None Green spaces (300 m) 0.0006052 0.8191236
21272 cg17155499 chr8:11644644 NEIL2 hs_mibp_madj_Log2 MiBP 0.0005205 0.8191236
21507 cg08447380 chr8:8185703 PRAGMIN h_legume_preg_Ter Legumes intake 0.0003115 0.8191236
22032 cg09460231 chr8:10736649 hs_pfhxs_m_Log2 PFHXS 0.0008149 0.8191236
22034 cg09460231 chr8:10736649 hs_pfoa_m_Log2 PFOA 0.0003938 0.8191236
24384 cg27100760 chr8:10708248 h_frichness300_preg_None Facility richness (300m) 0.0003419 0.8191236
25241 cg00348858 chr16:28858442 TUFM h_trafnear_preg_pow1over3 Traffic density on nearest road 0.0007075 0.8191236
26131 cg02195680 chr16:28519566 IL27 hs_tl_mdich_None Thallium 0.0005764 0.8191236
29238 cg22968622 chr17:43663579 h_thm_preg_Log Water THMs 0.0009173 0.8191236
29331 cg12609785 chr17:43660871 h_thm_preg_Log Water THMs 0.0009579 0.8191236
29424 cg19832721 chr17:44249866 KIAA1267 h_thm_preg_Log Water THMs 0.0009350 0.8191236
31637 cg26855231 chr17:44249543 KIAA1267 h_folic_t1_None Folic acid supplementation 0.0009498 0.8191236
32151 cg02301815 chr17:44249491 KIAA1267 hs_mepa_madj_Log2 MEPA 0.0005621 0.8191236
32281 cg24203758 chr17:43507018 SH3D20 h_clf_preg_Log Water Chloroform 0.0004701 0.8191236
32385 cg13947929 chr17:43863356 CRHR1 h_humidity_t1_None Humidity (t1) 0.0009737 0.8191236
32396 cg13947929 chr17:43863356 CRHR1 h_pm25_ratio_preg_None PM2.5 (preg) 0.0009218 0.8191236
33575 cg08358943 chr17:44889584 WNT3 e3_asmokyn_p_None Active smoking (preg) 0.0008655 0.8191236
37187 cg11969213 chr17:43324322 LOC100133991;FMNL1 hs_pcb138_madj_Log2 PCB 138 0.0003928 0.8191236
38981 cg16734549 chr17:43488551 ARHGAP27 h_fastfood_preg_Ter Fastfood intake 0.0006613 0.8191236
40470 cg12297030 chr17:43662878 h_fdensity300_preg_Log Facility density (300m) 0.0008056 0.8191236

2.4 Association between MDE genes and MDM CpG sites with human traits

The MDE genes and MDM CpG sites that are associated with human traits (p<0.01)are shown in Table 18 for inversion 8p23.1, in Table 19 for inversion 16p11.2, and in Table 20 for inversion 17q21.31.


Table 18: Mean differentially expressed genes and mean differentially methylated CpG sites from inversion 8p23.1 associated with obesity-related and neurological human traits.
Inversion Type_analysis Feature Diff Location Gene_Symbol Type_phenotype Phenotype Phenotype_abrev p.value
22 8p23.1 Mean TC08000099.hg.1 G chr8:12051976-12053789 FAM85A Obesity-related hs_totchol_c_None Total Cholesterol 0.0084915
26 8p23.1 Mean TC08000067.hg.1 G chr8:9046509-9060364 BC017578 Obesity-related hs_totchol_c_None Total Cholesterol 0.0091302
85 8p23.1 Mean cg12568669 G chr8:11666485 FDFT1 Obesity-related hs_phospho_c_None Phospholipids 0.0031661
86 8p23.1 Mean cg12568669 G chr8:11666485 FDFT1 Obesity-related hs_totchol_c_None Total Cholesterol 0.0030220
89 8p23.1 Mean cg11548083 G chr8:10208156 MSRA Obesity-related hs_phospho_c_None Phospholipids 0.0072123
101 8p23.1 Mean cg02711665 G chr8:11664728 FDFT1 Obesity-related hs_phospho_c_None Phospholipids 0.0071036
102 8p23.1 Mean cg02711665 G chr8:11664728 FDFT1 Obesity-related hs_totchol_c_None Total Cholesterol 0.0024376
161 8p23.1 Mean cg21725652 G chr8:10918152 XKR6 Obesity-related hs_phospho_c_None Phospholipids 0.0012344
182 8p23.1 Mean cg03399933 G chr8:11205972 TDH Obesity-related hs_totchol_c_None Total Cholesterol 0.0061776
210 8p23.1 Mean cg04654363 G chr8:8581213 Obesity-related hs_totchol_c_None Total Cholesterol 0.0089742
230 8p23.1 Mean cg05753693 G chr8:10192930 MSRA Obesity-related hs_totchol_c_None Total Cholesterol 0.0055762
232 8p23.1 Mean cg05753693 G chr8:10192930 MSRA Obesity-related e3_pi_None Ponderal index 0.0016517
246 8p23.1 Mean cg18303581 G chr8:8239485 PRAGMIN Obesity-related hs_totchol_c_None Total Cholesterol 0.0056206
254 8p23.1 Mean cg00074818 G chr8:8560427 CLDN23 Obesity-related hs_totchol_c_None Total Cholesterol 0.0079234
285 8p23.1 Mean cg17475643 G chr8:10261972 MSRA Obesity-related hs_phospho_c_None Phospholipids 0.0008020
286 8p23.1 Mean cg17475643 G chr8:10261972 MSRA Obesity-related hs_totchol_c_None Total Cholesterol 0.0001241
315 8p23.1 Mean cg18237548 G chr8:8860050 ERI1 Obesity-related e3_bwc_None Birth weight 0.0068570
369 8p23.1 Mean cg18461678 G chr8:10472980 RP1L1 Obesity-related hs_phospho_c_None Phospholipids 0.0036112
376 8p23.1 Mean cg12618270 G chr8:8667411 MFHAS1 Obesity-related e3_pi_None Ponderal index 0.0061258
389 8p23.1 Mean cg03617420 G chr8:10916666 XKR6 Obesity-related hs_phospho_c_None Phospholipids 0.0082839
515 8p23.1 Mean cg21088119 G chr8:11251471 C8orf12 Obesity-related e3_bwc_None Birth weight 0.0068403
639 8p23.1 Mean cg22917652 G chr8:10283152 MSRA Obesity-related e3_bwc_None Birth weight 0.0069590
645 8p23.1 Mean cg04413673 G chr8:10470278 RP1L1 Obesity-related hs_phospho_c_None Phospholipids 0.0057046
694 8p23.1 Mean cg01619129 G chr8:10697017 PINX1 Obesity-related hs_totchol_c_None Total Cholesterol 0.0055125
857 8p23.1 Mean cg13519851 G chr8:10916560 XKR6 Obesity-related hs_phospho_c_None Phospholipids 0.0040357
1006 8p23.1 Mean cg09500200 G chr8:9763033 Obesity-related hs_totchol_c_None Total Cholesterol 0.0079069
1131 8p23.1 Mean cg04015433 G chr8:8820844 Obesity-related e3_bwc_None Birth weight 0.0026194
1170 8p23.1 Mean cg05753693 G*E chr8:10192930 MSRA;MSRA;MSRA Obesity-related hs_totchol_c_None Total Cholesterol 0.0055762
1172 8p23.1 Mean cg05753693 G*E chr8:10192930 MSRA;MSRA;MSRA Obesity-related e3_pi_None Ponderal index 0.0016517

Table 19: Mean differentially expressed genes and mean differentially methylated CpG sites from inversion 16p11.2 associated with obesity-related and neurological human traits.
Inversion Type_analysis Feature Diff Location Gene_Symbol Type_phenotype Phenotype Phenotype_abrev p.value
1212 16p11.2 Mean TC16000986.hg.1 G chr16:28390900-28437775 EIF3CL;EIF3C Obesity-related hs_creatinine_c_None Creatinine 0.0034940
1213 16p11.2 Mean TC16000305.hg.1 G chr16:28699879-28747053 EIF3C;EIF3CL Obesity-related hs_creatinine_c_None Creatinine 0.0041999
1231 16p11.2 Mean cg05683445 G chr16:28303182 SBK1 Obesity-related hs_creatinine_c_None Creatinine 0.0097212
1274 16p11.2 Mean TC16000986.hg.1 G*E chr16:28390900-28437775 EIF3CL;EIF3C Obesity-related hs_creatinine_c_None Creatinine 0.0034940
1275 16p11.2 Mean TC16000305.hg.1 G*E chr16:28699879-28747053 EIF3C;EIF3CL Obesity-related hs_creatinine_c_None Creatinine 0.0041999
1286 16p11.2 Mean TC16000994.hg.1 G chr16:28853732-28857729 TUFM;MIR4721 Neurological hs_nhitcolors1 number of hits colors 1-back 0.0010935
1316 16p11.2 Mean cg09046979 G chr16:28333134 SBK1 Neurological hs_nhitcolors1 number of hits colors 1-back 0.0084540
1331 16p11.2 Mean cg00348858 G chr16:28858442 TUFM Neurological hs_Esc_AD NA 0.0010217
1425 16p11.2 Mean cg04968132 G*E chr16:27560915 GTF3C1;KIAA0556 Neurological hs_Esc_AD NA 0.0016233

Table 20: Mean differentially expressed genes and mean differentially methylated CpG sites from inversion 17q21.31 associated with obesity-related and neurological human traits.
Inversion Type_analysis Feature Diff Location Gene_Symbol Type_phenotype Phenotype Phenotype_abrev p.value
1479 17q21.31 Mean TC17001603.hg.1 G chr17:43578684-43597889 LRRC37A4P Neurological hs_nhitcolors3 number of hits colors 3-back 0.0080836
1503 17q21.31 Mean cg05159804 G chr17:44343776 Neurological hs_nhitcolors3 number of hits colors 3-back 0.0051687
1508 17q21.31 Mean cg05159804 G chr17:44343776 Neurological hs_sum_non_domHand Sum of the 2 trials nondominant hand 0.0072184
1516 17q21.31 Mean cg22968622 G chr17:43663579 Neurological hs_sum_non_domHand Sum of the 2 trials nondominant hand 0.0023492
1524 17q21.31 Mean cg12609785 G chr17:43660871 Neurological hs_sum_non_domHand Sum of the 2 trials nondominant hand 0.0004113
1528 17q21.31 Mean cg19832721 G chr17:44249866 KIAA1267 Neurological hs_accuracy_colors1 Percentage of correct responses (hits and correct rejections) colors 1-back 0.0097596
1532 17q21.31 Mean cg19832721 G chr17:44249866 KIAA1267 Neurological hs_sum_non_domHand Sum of the 2 trials nondominant hand 0.0085330
1534 17q21.31 Mean cg08113562 G chr17:43508428 SH3D20 Neurological hs_nmisscolors1 number of miss colors 1-back 0.0082713
1535 17q21.31 Mean cg08113562 G chr17:43508428 SH3D20 Neurological hs_nhitcolors3 number of hits colors 3-back 0.0095101
1548 17q21.31 Mean cg09764761 G chr17:44105544 MAPT Neurological hs_sum_non_domHand Sum of the 2 trials nondominant hand 0.0038260
1550 17q21.31 Mean cg07368061 G chr17:44090862 MAPT Neurological hs_nmisscolors1 number of miss colors 1-back 0.0036959
1551 17q21.31 Mean cg07368061 G chr17:44090862 MAPT Neurological hs_nhitcolors3 number of hits colors 3-back 0.0036519
1552 17q21.31 Mean cg07368061 G chr17:44090862 MAPT Neurological hs_accuracy_colors1 Percentage of correct responses (hits and correct rejections) colors 1-back 0.0073823
1553 17q21.31 Mean cg07368061 G chr17:44090862 MAPT Neurological hs_dcolors1 detectability colors 1-back 0.0063345
1558 17q21.31 Mean cg01341218 G chr17:43662625 Neurological hs_nmisscolors1 number of miss colors 1-back 0.0012065
1561 17q21.31 Mean cg01341218 G chr17:43662625 Neurological hs_dcolors1 detectability colors 1-back 0.0046461
1604 17q21.31 Mean cg22433210 G chr17:43662623 Neurological hs_sum_non_domHand Sum of the 2 trials nondominant hand 0.0043393
1621 17q21.31 Mean cg27503360 G chr17:43890749 CRHR1 Neurological hs_nfacolors1 number of false alarms colors 1-back 0.0007558
1622 17q21.31 Mean cg27503360 G chr17:43890749 CRHR1 Neurological hs_nmisscolors1 number of miss colors 1-back 0.0003260
1624 17q21.31 Mean cg27503360 G chr17:43890749 CRHR1 Neurological hs_accuracy_colors1 Percentage of correct responses (hits and correct rejections) colors 1-back 0.0000530
1625 17q21.31 Mean cg27503360 G chr17:43890749 CRHR1 Neurological hs_dcolors1 detectability colors 1-back 0.0000575
1668 17q21.31 Mean cg08670715 G chr17:44341754 Neurological hs_sum_non_domHand Sum of the 2 trials nondominant hand 0.0034266
1687 17q21.31 Mean cg07368127 G chr17:44230994 KIAA1267 Neurological hs_nhitcolors3 number of hits colors 3-back 0.0065754
1733 17q21.31 Mean cg24063856 G chr17:43863303 CRHR1 Neurological hs_nfacolors1 number of false alarms colors 1-back 0.0014963
1736 17q21.31 Mean cg24063856 G chr17:43863303 CRHR1 Neurological hs_accuracy_colors1 Percentage of correct responses (hits and correct rejections) colors 1-back 0.0057192
1740 17q21.31 Mean cg24063856 G chr17:43863303 CRHR1 Neurological hs_sum_non_domHand Sum of the 2 trials nondominant hand 0.0065917
1785 17q21.31 Mean cg13947929 G chr17:43863356 CRHR1 Neurological hs_dcolors1 detectability colors 1-back 0.0066662
1863 17q21.31 Mean cg06491244 G chr17:44851046 WNT3 Neurological hs_nhitcolors3 number of hits colors 3-back 0.0038096
1883 17q21.31 Mean cg14260695 G chr17:43506184 Neurological hs_dnumeros3 detectability numbers 3-back 0.0006076
1949 17q21.31 Mean cg00677574 G chr17:43221327 ACBD4 Neurological hs_nfacolors1 number of false alarms colors 1-back 0.0096534
1952 17q21.31 Mean cg00677574 G chr17:43221327 ACBD4 Neurological hs_accuracy_colors1 Percentage of correct responses (hits and correct rejections) colors 1-back 0.0091555
2077 17q21.31 Mean cg10701640 G chr17:43249399 Neurological hs_nfacolors1 number of false alarms colors 1-back 0.0034319
2080 17q21.31 Mean cg10701640 G chr17:43249399 Neurological hs_accuracy_colors1 Percentage of correct responses (hits and correct rejections) colors 1-back 0.0062625
2196 17q21.31 Mean cg11969213 G chr17:43324322 LOC100133991;FMNL1 Neurological hs_sum_non_domHand Sum of the 2 trials nondominant hand 0.0036855
2318 17q21.31 Mean cg10256219 G chr17:44270511 Neurological hs_nmisscolors1 number of miss colors 1-back 0.0033473

3 Mediation of variance differentially expressed genes

3.1 Variance Differential Analysis (VDA)

3.1.1 VDA for transcriptome

Inversion 8p23.1

The significant variance differentially methylated (VDM) genes for inversion 8p23.1 are shown in Table 21 and their distribution according to the inversion status is shown in Figure 23. The enrichment analysis of these genes has been performed and the results are presented in Figure 24.


Table 21: Variance differentially expressed genes for inversion 8p23.1
Inversion Type_analysis Transcript Location Gene_Symbol model adj.p.value DiffLevene_logFC
137 8p23.1 Variance TC08000093.hg.1 chr8:11653082-11696818 FDFT1 dominant 0.0218711 -0.0271569
149 8p23.1 Variance TC08000087.hg.1 chr8:11351510-11422113 BLK recessive 0.0001042 0.0539874
1105 8p23.1 Variance TC08000975.hg.1 chr8:11278972-11324276 FAM167A recessive 0.0005347 0.0335541
Enrichment analysis results for variance differentially expressed (VDE) genes for inversion 8p23.1. The colour depends on the p-value adjusted and the size of the dot indicates the number of counts. A) Results using KEGG database; B) Results using DisGeNET database; c) Results using GO database.

Figure 23: Enrichment analysis results for variance differentially expressed (VDE) genes for inversion 8p23.1
The colour depends on the p-value adjusted and the size of the dot indicates the number of counts. A) Results using KEGG database; B) Results using DisGeNET database; c) Results using GO database.

Box-plot representation for the variance differentially expressed genes in inversion 8p23.1. There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Figure 24: Box-plot representation for the variance differentially expressed genes in inversion 8p23.1
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Inversion 16p11.2

In the case of the 16p11.2 region, Table 22 reveals the VDM genes and Figure 26 shows the distribution of their gene expression. The results of the enrichment analysis are displayed in Figure 25.


Table 22: Variance differentially expressed genes for inversion 16p11.2
Inversion Type_analysis Transcript Location Gene_Symbol model adj.p.value DiffLevene_logFC
1109 16p11.2 Variance TC16000994.hg.1 chr16:28853732-28857729 TUFM;MIR4721 recessive 0.0000000 0.0854456
1110 16p11.2 Variance TC16000303.hg.1 chr16:28565247-28603111 CCDC101 recessive 0.0055758 0.0414499
1112 16p11.2 Variance TC16000314.hg.1 chr16:28986093-29002104 LAT;SPNS1 recessive 0.0070762 0.0199462
Enrichment analysis results for variance differentially expressed (VDE) genes for inversion 16p11.2. The colour depends on the p-value adjusted and the size of the dot indicates the number of counts. A) Results using KEGG database; B) Results using DisGeNET database; c) Results using GO database.

Figure 25: Enrichment analysis results for variance differentially expressed (VDE) genes for inversion 16p11.2
The colour depends on the p-value adjusted and the size of the dot indicates the number of counts. A) Results using KEGG database; B) Results using DisGeNET database; c) Results using GO database.

Box-plot representation for the variance differentially expressed genes in inversion 16p11.2. There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Figure 26: Box-plot representation for the variance differentially expressed genes in inversion 16p11.2
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Inversion 17q21.31

The polymorphic inversion 17q21.31 changes the variance expression levels of the genes that appear in Table 23. Figures 28 and 29 illustrate the gene expression distribution of these genes. The enrichment analysis revealed the results present in Figure 27.


Table 23: Variance differentially expressed genes for inversion 17q21.31
Inversion Type_analysis Transcript Location Gene_Symbol model adj.p.value DiffLevene_logFC
125 17q21.31 Variance TC17000598.hg.1 chr17:44450179-44500463 NSFP1 additive 0.0000000 -0.1340094
127 17q21.31 Variance TC17001608.hg.1 chr17:43677491-43679748 LOC644172 additive 0.0000000 0.0570190
129 17q21.31 Variance TC17000600.hg.1 chr17:44668035-44834830 NSF;NSFP1 additive 0.0000000 -0.0734839
133 17q21.31 Variance TC17001603.hg.1 chr17:43578684-43597889 LRRC37A4P additive 0.0000009 0.0408847
135 17q21.31 Variance TC17001613.hg.1 chr17:44594068-44657088 ARL17A additive 0.0000018 -0.0414159
136 17q21.31 Variance TC17001612.hg.1 chr17:44363862-44439163 ARL17A;ARL17B additive 0.0000018 -0.0393735
186 17q21.31 Variance TC17000596.hg.1 chr17:44270939-44274089 KANSL1-AS1 dominant 0.0000351 0.0483197
140 17q21.31 Variance TC17001617.hg.1 chr17:45098946-45099089 LOC51326 additive 0.0123146 -0.0272143
187 17q21.31 Variance TC17000599.hg.1 chr17:44590076-44633016 LRRC37A2 dominant 0.0013743 -0.0432640
Enrichment analysis results for variance differentially expressed (VDE) genes for inversion 17q21.31. The colour depends on the p-value adjusted and the size of the dot indicates the number of counts. A) Results using KEGG database; B) Results using DisGeNET database; c) Results using GO database.

Figure 27: Enrichment analysis results for variance differentially expressed (VDE) genes for inversion 17q21.31
The colour depends on the p-value adjusted and the size of the dot indicates the number of counts. A) Results using KEGG database; B) Results using DisGeNET database; c) Results using GO database.

Box-plot representation for the variance differentially expressed genes in inversion 17q21.31 (1). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Figure 28: Box-plot representation for the variance differentially expressed genes in inversion 17q21.31 (1)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Box-plot representation for the variance differentially expressed genes in inversion 17q21.31 (2). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

Figure 29: Box-plot representation for the variance differentially expressed genes in inversion 17q21.31 (2)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene, as well as the most significant model of inheritance with the corresponding p-value.

3.1.2 VDA for methylome

Inversion 8p23.1

The VDM CpG sites for inversion 8p23.1 are shown in Table 24 and their respective genes are enriched in functions revealed in Figure 30.


Table 24: Variance differentially methylated CpG sites for inversion 8p23.1
Inversion Type_analysis CpG Location Gene_Symbol model adj.p.value DiffLevene_logFC
831 8p23.1 Variance cg26670620 chr8:12244544 FAM66A dominant 0.0000000 -0.2169291
416 8p23.1 Variance cg23217680 chr8:9029456 additive 0.0000000 0.0475589
832 8p23.1 Variance cg12792075 chr8:12244565 FAM66A dominant 0.0000000 -0.3205989
418 8p23.1 Variance cg07042170 chr8:8831422 additive 0.0000000 -0.0385251
419 8p23.1 Variance cg01274122 chr8:8749938 MFHAS1 additive 0.0000000 -0.0384226
420 8p23.1 Variance cg23361275 chr8:8749919 MFHAS1 additive 0.0000000 -0.0434153
833 8p23.1 Variance cg02771117 chr8:11279352 FAM167A;C8orf12 dominant 0.0000000 -0.1105227
422 8p23.1 Variance cg10220992 chr8:11324327 FAM167A additive 0.0000001 0.0295230
423 8p23.1 Variance cg02525722 chr8:10404760 additive 0.0000004 -0.0730879
840 8p23.1 Variance cg10613815 chr8:11283299 C8orf12;FAM167A dominant 0.0000013 -0.0967995
425 8p23.1 Variance cg26161004 chr8:11413186 BLK additive 0.0000045 0.0146637
1178 8p23.1 Variance cg00074818 chr8:8560427 CLDN23 recessive 0.0000046 0.0410251
427 8p23.1 Variance cg14702231 chr8:11413234 BLK additive 0.0000142 0.0186140
1181 8p23.1 Variance cg04025970 chr8:8727303 MFHAS1 recessive 0.0000100 0.0661478
1183 8p23.1 Variance cg17329886 chr8:10513629 RP1L1 recessive 0.0000211 0.0916817
1182 8p23.1 Variance cg26100214 chr8:8580376 recessive 0.0000157 0.0394348
1174 8p23.1 Variance cg02319733 chr8:10282549 MSRA recessive 0.0000001 0.0284070
432 8p23.1 Variance cg06671706 chr8:8559999 CLDN23 additive 0.0000851 0.0409551
433 8p23.1 Variance cg22799963 chr8:11536778 additive 0.0002730 0.0158261
434 8p23.1 Variance cg09768257 chr8:11628346 NEIL2 additive 0.0003564 -0.0215618
837 8p23.1 Variance cg16038868 chr8:10192619 MSRA dominant 0.0000000 -0.0320286
1176 8p23.1 Variance cg12940923 chr8:10282607 MSRA recessive 0.0000006 0.0491409
1191 8p23.1 Variance cg00115954 chr8:11536551 recessive 0.0005374 0.0184790
438 8p23.1 Variance cg08012294 chr8:11723816 CTSB additive 0.0011132 -0.0212917
439 8p23.1 Variance cg00870242 chr8:10530148 C8orf74 additive 0.0013832 -0.0099356
835 8p23.1 Variance cg02711665 chr8:11664728 FDFT1 dominant 0.0000000 -0.0441326
848 8p23.1 Variance cg02840367 chr8:11660030 FDFT1 dominant 0.0004766 -0.0610700
846 8p23.1 Variance cg14257676 chr8:10192642 MSRA dominant 0.0001814 -0.0258372
1192 8p23.1 Variance cg00873037 chr8:11626984 NEIL2 recessive 0.0025521 0.0427238
444 8p23.1 Variance cg07761646 chr8:7113462 FAM90A13;FAM90A14 additive 0.0109105 0.0322748
445 8p23.1 Variance cg26966828 chr8:10208257 MSRA additive 0.0198429 0.0154769
836 8p23.1 Variance cg12568669 chr8:11666485 FDFT1 dominant 0.0000000 -0.0788849
844 8p23.1 Variance cg01383082 chr8:11323474 FAM167A dominant 0.0001279 -0.0338096
850 8p23.1 Variance cg13601595 chr8:10468038 RP1L1 dominant 0.0087112 -0.0161153
853 8p23.1 Variance cg11302791 chr8:10635419 PINX1 dominant 0.0183353 -0.0304665
854 8p23.1 Variance cg23584735 chr8:10686021 PINX1 dominant 0.0199375 0.0136403
855 8p23.1 Variance cg21701351 chr8:11374773 BLK dominant 0.0199375 -0.0287833
857 8p23.1 Variance cg04541228 chr8:11625883 NEIL2 dominant 0.0203900 -0.0196985
1171 8p23.1 Variance cg11548083 chr8:10208156 MSRA recessive 0.0000000 0.0522596
1184 8p23.1 Variance cg12395012 chr8:11607386 GATA4 recessive 0.0000271 0.0405963
1186 8p23.1 Variance cg15426459 chr8:11813211 recessive 0.0000769 0.0406807
1187 8p23.1 Variance cg11465442 chr8:11832261 DEFB136 recessive 0.0001216 0.0325567
1188 8p23.1 Variance cg06620390 chr8:10192943 MSRA recessive 0.0002587 0.0316767
1190 8p23.1 Variance cg08265495 chr8:11212668 TDH recessive 0.0004357 0.0435098
1193 8p23.1 Variance cg20449619 chr8:10581784 SOX7 recessive 0.0027532 0.0372796
1194 8p23.1 Variance cg03007522 chr8:11562685 GATA4 recessive 0.0033390 0.0206992
1196 8p23.1 Variance cg00629382 chr8:10268916 MSRA recessive 0.0052549 0.0212186
1201 8p23.1 Variance cg08841257 chr8:10191002 MSRA recessive 0.0117684 0.0287605
1204 8p23.1 Variance cg27598632 chr8:7686204 DEFB106B;DEFB106A recessive 0.0189025 0.0322949
1205 8p23.1 Variance cg08196601 chr8:12869553 C8orf79 recessive 0.0220116 0.0221846
Enrichment analysis results for variance differentially methylated (VDM) genes in inversion 8p23.1 using GO database.

Figure 30: Enrichment analysis results for variance differentially methylated (VDM) genes in inversion 8p23.1 using GO database

Inversion 16p11.2

The CpG sites that appear in Table 25 are VMD according to the 16p11.2 region status. Moreover, the enrichment of the genes that contain these CpG sites is presented in Figure 31.


Table 25: Variance differentially methylated CpG sites for inversion 16p11.2
Inversion Type_analysis CpG Location Gene_Symbol model adj.p.value DiffLevene_logFC
1206 16p11.2 Variance cg09046979 chr16:28333134 SBK1 recessive 0.0000000 0.1680773
447 16p11.2 Variance cg12743398 chr16:28609531 SULT1A2 additive 0.0000000 -0.0626002
448 16p11.2 Variance cg02358434 chr16:28995271 SPNS1;LAT additive 0.0145275 0.0094420
1207 16p11.2 Variance cg04270652 chr16:28608894 SULT1A2 recessive 0.0000000 0.0738242
1208 16p11.2 Variance cg27413008 chr16:28519597 IL27 recessive 0.0000000 0.0682448
1209 16p11.2 Variance cg26624097 chr16:28620651 SULT1A1 recessive 0.0001035 0.0621461
1210 16p11.2 Variance cg00348858 chr16:28858442 TUFM recessive 0.0001397 0.0351291
1211 16p11.2 Variance cg02896250 chr16:28305533 SBK1 recessive 0.0009491 0.0250289
1212 16p11.2 Variance cg26603685 chr16:28620355 SULT1A1 recessive 0.0031343 0.0325097
1213 16p11.2 Variance cg26792089 chr16:28518200 IL27 recessive 0.0062890 0.0169983
1214 16p11.2 Variance cg01378222 chr16:28622494 SULT1A1 recessive 0.0079658 0.0366399
Enrichment analysis results for variance differentially methylated (VDM) genes in inversion 16p11.2. A) Results using KEGG database; B) Results for the enrichment using DisGeNET database; C) Enrichment results using GO.

Figure 31: Enrichment analysis results for variance differentially methylated (VDM) genes in inversion 16p11.2
A) Results using KEGG database; B) Results for the enrichment using DisGeNET database; C) Enrichment results using GO.

Inversion 17q21.31

Table 26 displays the CpG sites VMD depending on the inversion 17q21.31 genotype. Their respective genes have been used for an enrichment analysis which results are shown in Figure 32.


Table 26: Variance differentially methylated CpG sites for inversion 17q21.31
Inversion Type_analysis CpG Location Gene_Symbol model adj.p.value DiffLevene_logFC
859 17q21.31 Variance cg22968622 chr17:43663579 dominant 0.0000000 0.6499105
450 17q21.31 Variance cg12609785 chr17:43660871 additive 0.0000000 0.3727500
451 17q21.31 Variance cg08113562 chr17:43508428 SH3D20 additive 0.0000000 0.1665435
1216 17q21.31 Variance cg05159804 chr17:44343776 recessive 0.0000000 0.3924877
1217 17q21.31 Variance cg19832721 chr17:44249866 KIAA1267 recessive 0.0000000 0.3943881
454 17q21.31 Variance cg02665463 chr17:44657154 ARL17A additive 0.0000000 -0.1754514
1220 17q21.31 Variance cg01341218 chr17:43662625 recessive 0.0000000 0.2161664
1219 17q21.31 Variance cg09764761 chr17:44105544 MAPT recessive 0.0000000 0.2088788
1224 17q21.31 Variance cg07368061 chr17:44090862 MAPT recessive 0.0000000 0.1488632
1222 17q21.31 Variance cg05301556 chr17:43971177 MAPT;LOC100128977 recessive 0.0000000 0.1246551
1225 17q21.31 Variance cg22433210 chr17:43662623 recessive 0.0000000 0.1676423
1227 17q21.31 Variance cg01882395 chr17:43717810 C17orf69 recessive 0.0000000 0.1007474
1223 17q21.31 Variance cg03954353 chr17:43715162 C17orf69;MGC57346 recessive 0.0000000 0.1307532
1226 17q21.31 Variance cg00891649 chr17:43972573 MAPT;LOC100130148;LOC100128977 recessive 0.0000000 0.1218721
1230 17q21.31 Variance cg23659289 chr17:43472725 ARHGAP27 recessive 0.0000000 0.0429529
464 17q21.31 Variance cg03209459 chr17:44604660 ARL17A;LRRC37A2 additive 0.0004157 -0.0345841
868 17q21.31 Variance cg05186793 chr17:44235520 KIAA1267 dominant 0.0000055 -0.0485384
1231 17q21.31 Variance cg19943578 chr17:43483527 ARHGAP27 recessive 0.0000000 0.0427597
467 17q21.31 Variance cg13465858 chr17:44204908 KIAA1267 additive 0.0012275 -0.0250799
468 17q21.31 Variance cg26250449 chr17:44195907 KIAA1267 additive 0.0075841 -0.0223583
1233 17q21.31 Variance cg05772917 chr17:44027251 MAPT recessive 0.0000007 0.0429338
874 17q21.31 Variance cg19872068 chr17:44250734 KIAA1267 dominant 0.0075102 -0.0177977
471 17q21.31 Variance cg00480298 chr17:44068857 MAPT additive 0.0136062 0.0204525
472 17q21.31 Variance cg25246246 chr17:43503131 ARHGAP27 additive 0.0170279 -0.0096454
473 17q21.31 Variance cg03244997 chr17:43503144 ARHGAP27 additive 0.0188162 -0.0085639
1238 17q21.31 Variance cg12798194 chr17:43462791 recessive 0.0153532 0.0407342
1232 17q21.31 Variance cg14374015 chr17:44249569 KIAA1267 recessive 0.0000006 0.0690504
1234 17q21.31 Variance cg27503360 chr17:43890749 CRHR1 recessive 0.0000008 0.0358867
1235 17q21.31 Variance cg21214508 chr17:44248233 KIAA1267 recessive 0.0049900 0.0508209
1236 17q21.31 Variance cg04491389 chr17:44214771 KIAA1267 recessive 0.0080905 0.0499102
1237 17q21.31 Variance cg18410271 chr17:43472435 ARHGAP27 recessive 0.0086483 0.0153128
Enrichment analysis results for variance differentially methylated (VDM) in inversion 17q21.31. A) Enrichment results using DisGeNET; B) Results for the enrichment using GO database.

Figure 32: Enrichment analysis results for variance differentially methylated (VDM) in inversion 17q21.31
A) Enrichment results using DisGeNET; B) Results for the enrichment using GO database.

3.1.3 VDA for transcriptome using inversion*exposome interaction

The results of the VDA according to the genotype*exposure are displayed in Table 27 and Figures 33 and 34 for inverison 8p23.1, Table 28 and Figures 36 and 37 for inversion 16p11.2, and Table 29 and Figures 39 and 40 for inversion 17q21.31. The enrichment analysis results for the respective inversions are shown in Figures Figure 35, 38, and 41.

Inversion 8p23.1


Table 27: Variance differentially methylated CpG sites for interaction between inversion 8p23.1 and pregnancy exposome.
Exposure Exposure_abrev Family Inversion Type_analysis Transcript Location Gene_Symbol adj.p.value DiffLevene_logFC
8 h_ndvi100_preg_None NDVI (100 m) Natural Spaces 8p23.1 Variance TC08001807.hg.1 chr8:12435815-12438798 AX747590 0.0112863 -0.3297102
21 hs_mecpp_madj_Log2 MECPP Phthalates 8p23.1 Variance TC08000069.hg.1 chr8:9413422-9639856 TNKS 0.0073701 0.0160530
27 hs_meohp_madj_Log2 MEOHP Phthalates 8p23.1 Variance TC08000069.hg.1 chr8:9413422-9639856 TNKS 0.0085911 0.0140747
29 hs_mep_madj_Log2 MEP Phthalates 8p23.1 Variance TC08000987.hg.1 chr8:11994677-11996586 USP17L2 0.0472567 0.0149799
113 hs_mnbp_madj_Log2 MnBP Phthalates 8p23.1 Variance TC08000995.hg.1 chr8:12282913-12293915 FAM86B2;FAM86B1 0.0319913 0.0123571
114 hs_oxominp_madj_Log2 oxo-MiNP Phthalates 8p23.1 Variance TC08000056.hg.1 chr8:8086092-8102387 FAM86B3P 0.0157725 0.0117731
116 hs_pbde47_madj_Log2 PBDE 47 PBDEs 8p23.1 Variance TC08000053.hg.1 chr8:7812535-7866277 FAM66E 0.0455927 0.0122072
Plot representations for the variance differentially expressed genes when inversion 8p23.1 interacts with exposome (1). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Figure 33: Plot representations for the variance differentially expressed genes when inversion 8p23.1 interacts with exposome (1)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Plot representations for the variance differentially expressed genes when inversion 8p23.1 interacts with exposome (2). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Figure 34: Plot representations for the variance differentially expressed genes when inversion 8p23.1 interacts with exposome (2)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

GO enrichment analysis for variance differentially expressed (VDE) genes using genotype-environment interaction for inversion 8p23.1.

Figure 35: GO enrichment analysis for variance differentially expressed (VDE) genes using genotype-environment interaction for inversion 8p23.1

Inversion 16p11.2


Table 28: Variance differentially methylated CpG sites for interaction between inversion 16p11.2 and pregnancy exposome.
Exposure Exposure_abrev Family Inversion Type_analysis Transcript Location Gene_Symbol adj.p.value DiffLevene_logFC
5 h_landuseshan300_preg_None Land use (300m) Building Environment 16p11.2 Variance TC16000303.hg.1 chr16:28565247-28603111 CCDC101 0.0411589 -0.1501837
9 h_pm25_ratio_preg_None PM2.5 (preg) Air Pollution 16p11.2 Variance TC16000983.hg.1 chr16:28109316-28223190 XPO6 0.0405140 -0.0076731
11 h_walkability_mean_preg_None Walkability Building Environment 16p11.2 Variance TC16000981.hg.1 chr16:27798850-28074830 GSG1L 0.0229412 -0.1381578
18 hs_hcb_madj_Log2 HCB OCs 16p11.2 Variance TC16000979.hg.1 chr16:27471934-27561251 GTF3C1 0.0013072 0.0273696
22 hs_mehhp_madj_Log2 MEHHP Phthalates 16p11.2 Variance TC16000303.hg.1 chr16:28565247-28603111 CCDC101 0.0178208 0.0207063
23 hs_mehhp_madj_Log2 MEHHP Phthalates 16p11.2 Variance TC16000304.hg.1 chr16:28648975-28670003 NPIPB8;NPIPL1 0.0432203 0.0140482
24 hs_mehp_madj_Log2 MEHP Phthalates 16p11.2 Variance TC16000303.hg.1 chr16:28565247-28603111 CCDC101 0.0246590 0.0207599
25 hs_mehp_madj_Log2 MEHP Phthalates 16p11.2 Variance TC16000986.hg.1 chr16:28390900-28437775 EIF3CL;EIF3C 0.0372016 0.0446434
26 hs_mehp_madj_Log2 MEHP Phthalates 16p11.2 Variance TC16000305.hg.1 chr16:28699879-28747053 EIF3C;EIF3CL 0.0372016 0.0451882
110 hs_mibp_madj_Log2 MiBP Phthalates 16p11.2 Variance TC16001479.hg.1 chr16:29466412-29476301 SLX1A-SULT1A3 0.0416940 -0.0406769
111 hs_mibp_madj_Log2 MiBP Phthalates 16p11.2 Variance TC16000321.hg.1 chr16:29465822-29476301 SLX1B;SULT1A4;SULT1A3;SLX1B-SULT1A4;SLX1A;SLX1A-SULT1A3 0.0418980 -0.0199711
118 hs_pcb138_madj_Log2 PCB 138 OCs 16p11.2 Variance TC16000979.hg.1 chr16:27471934-27561251 GTF3C1 0.0115090 0.0249389
Plot representations for the variance differentially expressed genes when inversion 16p11.2 interacts with exposome (1). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Figure 36: Plot representations for the variance differentially expressed genes when inversion 16p11.2 interacts with exposome (1)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Plot representations for the variance differentially expressed genes when inversion 16p11.2 interacts with exposome (2). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Figure 37: Plot representations for the variance differentially expressed genes when inversion 16p11.2 interacts with exposome (2)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

GO enrichment analysis for variance differentially expressed (VDE) genes using genotype-environment interaction for inversion 16p11.2.

Figure 38: GO enrichment analysis for variance differentially expressed (VDE) genes using genotype-environment interaction for inversion 16p11.2

Inversion 17q21.31


Table 29: Variance differentially methylated CpG sites for interaction between inversion 17q21.31 and pregnancy exposome.
Exposure Exposure_abrev Family Inversion Type_analysis Transcript Location Gene_Symbol adj.p.value DiffLevene_logFC
1 h_clf_preg_Log Water Chloroform Water DBPs 17q21.31 Variance TC17000581.hg.1 chr17:43238264-43247406 HEXIM2 0.0275387 0.0127057
2 h_greenyn300_preg_None Green spaces (300 m) Natural Spaces 17q21.31 Variance TC17002876.hg.1 chr17:43861646-43913194 CRHR1 0.0252909 -0.0117903
14 hs_cd_m_Log2 Cadmium Metals 17q21.31 Variance TC17001599.hg.1 chr17:43404732-43404863 RNA5SP443 0.0451536 -0.0347179
19 hs_k_m_Log2 K Essential minerals 17q21.31 Variance TC17000576.hg.1 chr17:42977084-42982758 CCDC103;FAM187A 0.0075601 0.0678150
20 hs_mbzp_madj_Log2 MBzP Phthalates 17q21.31 Variance TC17001597.hg.1 chr17:43331760-43339479 SPATA32 0.0118166 -0.0082706
117 hs_oxominp_madj_Log2 oxo-MiNP Phthalates 17q21.31 Variance TC17001588.hg.1 chr17:42982993-42992920 GFAP;AK124465 0.0301282 0.0056141
119 hs_pcb138_madj_Log2 PCB 138 OCs 17q21.31 Variance TC17000577.hg.1 chr17:43138680-43186382 NMT1 0.0476627 -0.0222118
Plot representations for the variance differentially expressed genes when inversion 17q21.31 interacts with exposome (1). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Figure 39: Plot representations for the variance differentially expressed genes when inversion 17q21.31 interacts with exposome (1)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Plot representations for the variance differentially expressed genes when inversion 17q21.31 interacts with exposome (2). There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

Figure 40: Plot representations for the variance differentially expressed genes when inversion 17q21.31 interacts with exposome (2)
There are shown the gene expression distributions for the different inversion genotypes: homozygous inverted (I/I), heterozygous (N/I), and homozygous non-inverted (N/N). On the top of each plot, it is displayed the name of the differentially expressed gene with the corresponding p-value.

GO enrichment analysis for variance differentially expressed (VDE) genes using genotype-environment interaction for inversion 17q21.31.

Figure 41: GO enrichment analysis for variance differentially expressed (VDE) genes using genotype-environment interaction for inversion 17q21.31

3.1.4 VDA for methylome using inversion*exposome interaction

The VDA for methylome using the interaction between the inversion at 8p23.1 and exposome has revelaed the different variance methylation of the CpG sites that are displayed in Table 30. The enrichment results of the genes that contain these CpG sites are illustrated in Figure 42.The same has been implemented for inversion 16p11.2 and inversion 17q21.31 and the results are shown in Table 31 and Figure 43, and Table 32 and Figure 44, respectively.

Inversion 8p23.1


Table 30: Variance differentially methylated CpG sites according to the interaction between inverison 8p23.1 and pregnancy exposome
Exposure Exposure_abrev Family Inversion Type_analysis CpG Location Gene_Symbol adj.p.value DiffLevene_logFC
3 e3_alcpreg_yn_None Alcohol intake Lifestyle 8p23.1 Variance cg23361275 chr8:8749919 MFHAS1 0.0015519 0.0820723
4 e3_alcpreg_yn_None Alcohol intake Lifestyle 8p23.1 Variance cg26670620 chr8:12244544 FAM66A 0.0440143 0.1592449
5 e3_asmokyn_p_None Active smoking (preg) Tobacco Smoke 8p23.1 Variance cg10613815 chr8:11283299 C8orf12;FAM167A 0.0388690 0.1487399
7 h_blueyn300_preg_None Blue spaces (300 m) Natural Spaces 8p23.1 Variance cg06952801 chr8:10460235 0.0009129 0.2954732
8 h_blueyn300_preg_None Blue spaces (300 m) Natural Spaces 8p23.1 Variance cg06032483 chr8:9599206 MIR597;TNKS 0.0009129 0.0589440
9 h_blueyn300_preg_None Blue spaces (300 m) Natural Spaces 8p23.1 Variance cg02771117 chr8:11279352 FAM167A;C8orf12 0.0017817 0.2068133
13 h_connind300_preg_Sqrt Connectivity (300m) Building Environment 8p23.1 Variance cg08115957 chr8:11838532 DEFB135 0.0063598 0.0113932
15 h_fastfood_preg_Ter Fastfood intake Lifestyle 8p23.1 Variance cg08115957 chr8:11838532 DEFB135 0.0000083 0.2636294
16 h_fdensity300_preg_Log Facility density (300m) Building Environment 8p23.1 Variance cg18050997 chr8:8176225 PRAGMIN 0.0137751 0.0385449
19 h_folic_t1_None Folic acid supplementation Lifestyle 8p23.1 Variance cg18718312 chr8:11772119 0.0361960 0.0288110
22 h_fruit_preg_Ter Fruits intake Lifestyle 8p23.1 Variance cg12792075 chr8:12244565 FAM66A 0.0378623 0.2934985
23 h_fruit_preg_Ter Fruits intake Lifestyle 8p23.1 Variance cg10613815 chr8:11283299 C8orf12;FAM167A 0.0378623 0.1375314
24 h_greenyn300_preg_None Green spaces (300 m) Natural Spaces 8p23.1 Variance cg10613815 chr8:11283299 C8orf12;FAM167A 0.0002295 -0.1706376
25 h_humidity_t1_None Humidity (t1) Meteorological 8p23.1 Variance cg21002223 chr8:8747452 MFHAS1 0.0302253 -0.0035800
27 h_legume_preg_Ter Legumes intake Lifestyle 8p23.1 Variance cg22651416 chr8:10643634 PINX1 0.0325299 -0.2103315
31 h_trafload_preg_pow1over3 Road traffic load (100 m) Traffic 8p23.1 Variance cg14143728 chr8:9015622 0.0261573 0.0002424
33 h_walkability_mean_preg_None Walkability Building Environment 8p23.1 Variance cg22008625 chr8:10588386 SOX7 0.0049448 -0.2551065
34 h_walkability_mean_preg_None Walkability Building Environment 8p23.1 Variance cg08115957 chr8:11838532 DEFB135 0.0049448 0.6814331
35 hs_cd_m_Log2 Cadmium Metals 8p23.1 Variance cg01970784 chr8:10191983 MSRA;MSRA;MSRA 0.0311820 0.0353690
36 hs_co_m_Log2 Cobalt Metals 8p23.1 Variance cg05753693 chr8:10192930 MSRA;MSRA;MSRA 0.0216276 -0.0240518
38 hs_ddt_madj_Log2 DDT OCs 8p23.1 Variance cg07340894 chr8:8238774 PRAGMIN 0.0163915 0.0127018
39 hs_ddt_madj_Log2 DDT OCs 8p23.1 Variance cg24701369 chr8:9535308 TNKS 0.0163915 0.0156689
40 hs_dmp_madj_Log2 DMP OP Pesticides 8p23.1 Variance cg01035616 chr8:8235320 PRAGMIN 0.0142439 0.0216696
44 hs_mbzp_madj_Log2 MBzP Phthalates 8p23.1 Variance cg02519718 chr8:11251277 C8orf12 0.0314230 0.0117915
45 hs_mecpp_madj_Log2 MECPP Phthalates 8p23.1 Variance cg13601595 chr8:10468038 RP1L1 0.0005667 0.0245592
47 hs_mehhp_madj_Log2 MEHHP Phthalates 8p23.1 Variance cg13601595 chr8:10468038 RP1L1 0.0408846 0.0158393
48 hs_mehhp_madj_Log2 MEHHP Phthalates 8p23.1 Variance cg01383082 chr8:11323474 FAM167A 0.0408846 0.0240998
49 hs_meohp_madj_Log2 MEOHP Phthalates 8p23.1 Variance cg13601595 chr8:10468038 RP1L1 0.0016208 0.0207452
51 hs_mnbp_madj_Log2 MnBP Phthalates 8p23.1 Variance cg26886855 chr8:10694831 PINX1 0.0113143 0.0178850
52 hs_mnbp_madj_Log2 MnBP Phthalates 8p23.1 Variance cg04009108 chr8:7406299 0.0183098 0.0531549
54 hs_mo_m_Log2 Molybdenum Metals 8p23.1 Variance cg17886471 chr8:10339410 0.0013514 0.0949066
55 hs_mo_m_Log2 Molybdenum Metals 8p23.1 Variance cg02192555 chr8:9952926 MSRA;MSRA;MSRA 0.0246763 -0.0876695
56 hs_mo_m_Log2 Molybdenum Metals 8p23.1 Variance cg10866298 chr8:9760869 LOC157627 0.0246763 0.0666171
57 hs_mo_m_Log2 Molybdenum Metals 8p23.1 Variance cg19882315 chr8:11351846 BLK;BLK 0.0388953 0.0417569
60 hs_oxbe_madj_Log2 OXBE Phenols 8p23.1 Variance cg05870116 chr8:8643280 MFHAS1 0.0012419 0.0131867
61 hs_oxominp_madj_Log2 oxo-MiNP Phthalates 8p23.1 Variance cg02771117 chr8:11279352 FAM167A;C8orf12 0.0014269 0.0552437
63 hs_pbde47_madj_Log2 PBDE 47 PBDEs 8p23.1 Variance cg06952801 chr8:10460235 0.0166467 0.0586597
64 hs_pbde47_madj_Log2 PBDE 47 PBDEs 8p23.1 Variance cg02621357 chr8:11296980 FAM167A 0.0467747 0.0139473
74 hs_pfhxs_m_Log2 PFHXS PFASs 8p23.1 Variance cg15537082 chr8:9762300 MIR124-1;LOC157627 0.0000000 0.1129251
79 hs_pfna_m_Log2 PFNA PFASs 8p23.1 Variance cg12792075 chr8:12244565 FAM66A 0.0076081 0.2126663
80 hs_pfna_m_Log2 PFNA PFASs 8p23.1 Variance cg26670620 chr8:12244544 FAM66A 0.0476208 0.1199816
83 hs_pfos_m_Log2 PFOS PFASs 8p23.1 Variance cg15537082 chr8:9762300 MIR124-1;LOC157627 0.0021212 0.0819322
84 hs_pfos_m_Log2 PFOS PFASs 8p23.1 Variance cg26670620 chr8:12244544 FAM66A 0.0070993 0.1390674
85 hs_pfos_m_Log2 PFOS PFASs 8p23.1 Variance cg12792075 chr8:12244565 FAM66A 0.0070993 0.2104820
86 hs_pfos_m_Log2 PFOS PFASs 8p23.1 Variance cg23045373 chr8:11324048 FAM167A 0.0219238 -0.0385984
87 hs_pfunda_m_Log2 PFUNDA PFASs 8p23.1 Variance cg00690195 chr8:8915582 0.0015937 0.0339313
90 hs_prpa_madj_Log2 PRPA Phenols 8p23.1 Variance cg11557530 chr8:9911760 MSRA;MSRA 0.0400802 0.0075899
93 hs_tl_mdich_None Thallium Metals 8p23.1 Variance cg04815626 chr8:9912509 MSRA;MSRA 0.0000000 -0.3562787
94 hs_tl_mdich_None Thallium Metals 8p23.1 Variance cg14143728 chr8:9015622 0.0000000 -0.1703917
95 hs_tl_mdich_None Thallium Metals 8p23.1 Variance cg01660034 chr8:10259065 MSRA;MSRA;MSRA 0.0002209 -0.2791986
96 hs_tl_mdich_None Thallium Metals 8p23.1 Variance cg02724490 chr8:10488231 RP1L1 0.0084887 -0.0689882
99 hs_trcs_madj_Log2 TRCS Phenols 8p23.1 Variance cg12792075 chr8:12244565 FAM66A 0.0090429 -0.0446952
100 hs_trcs_madj_Log2 TRCS Phenols 8p23.1 Variance cg26670620 chr8:12244544 FAM66A 0.0181742 -0.0270895
Enrichment analysis for variance differentially methylated (VDM) genes using genotype-environment interaction for inversion 8p23.1. A) Results for the enrichment using KEGG database; B) Results for the enrichment using DisGeNET database; C) GO enrichment results.

Figure 42: Enrichment analysis for variance differentially methylated (VDM) genes using genotype-environment interaction for inversion 8p23.1
A) Results for the enrichment using KEGG database; B) Results for the enrichment using DisGeNET database; C) GO enrichment results.

Inversion 16p11.2


Table 31: Variance differentially methylated CpG sites according to the interaction between inverison 16p11.2 and pregnancy exposome
Exposure Exposure_abrev Family Inversion Type_analysis CpG Location Gene_Symbol adj.p.value DiffLevene_logFC
10 h_blueyn300_preg_None Blue spaces (300 m) Natural Spaces 16p11.2 Variance cg03328388 chr16:28886581 0.0000617 0.1339691
32 h_trafnear_preg_pow1over3 Traffic density on nearest road Traffic 16p11.2 Variance cg23797100 chr16:28996053 LAT;LAT;LAT;LAT 0.0418998 0.0019718
41 hs_dmtp_madj_Log2 DMTP OP Pesticides 16p11.2 Variance cg04413090 chr16:28302913 SBK1 0.0457651 0.0124660
62 hs_pb_m_Log2 Lead Metals 16p11.2 Variance cg03328388 chr16:28886581 0.0000000 0.1191119
75 hs_pfhxs_m_Log2 PFHXS PFASs 16p11.2 Variance cg00184016 chr16:28833823 ATXN2L;ATXN2L;ATXN2L;ATXN2L;ATXN2L 0.0000025 0.0413751
76 hs_pfhxs_m_Log2 PFHXS PFASs 16p11.2 Variance cg27027151 chr16:27461638 IL21R;IL21R;IL21R 0.0005652 0.0213302
77 hs_pfhxs_m_Log2 PFHXS PFASs 16p11.2 Variance cg09739165 chr16:27637519 KIAA0556 0.0283103 0.0246679
91 hs_prpa_madj_Log2 PRPA Phenols 16p11.2 Variance cg26624097 chr16:28620651 SULT1A1;SULT1A1;SULT1A1;SULT1A1;SULT1A1 0.0071522 -0.0135043
97 hs_tl_mdich_None Thallium Metals 16p11.2 Variance cg14791831 chr16:28565295 CCDC101;CCDC101 0.0071366 -0.1086587
98 hs_tl_mdich_None Thallium Metals 16p11.2 Variance cg04395184 chr16:28222866 XPO6;XPO6 0.0098270 -0.1232376
Enrichment analysis for variance differentially methylated (VDM) genes using genotype-environment interaction for inversion 16p11.2. A) Results for the enrichment using KEGG database; B) Results for the enrichment using DisGeNET database.

Figure 43: Enrichment analysis for variance differentially methylated (VDM) genes using genotype-environment interaction for inversion 16p11.2
A) Results for the enrichment using KEGG database; B) Results for the enrichment using DisGeNET database.

Inversion 17q21.31


Table 32: Variance differentially methylated CpG sites according to the interaction between inverison 17q21.31 and pregnancy exposome
Exposure Exposure_abrev Family Inversion Type_analysis CpG Location Gene_Symbol adj.p.value DiffLevene_logFC
11 h_bro_preg_Log Water Brominated THMs Water DBPs 17q21.31 Variance cg05772917 chr17:44027251 MAPT;MAPT;MAPT;MAPT;MAPT;MAPT 0.0393166 -0.0103595
37 hs_co_m_Log2 Cobalt Metals 17q21.31 Variance cg03928887 chr17:43200129 PLCD3 0.0000004 0.1100341
43 hs_k_m_Log2 K Essential minerals 17q21.31 Variance cg14178294 chr17:43109690 DCAKD;DCAKD 0.0036910 0.0867444
58 hs_mo_m_Log2 Molybdenum Metals 17q21.31 Variance cg03928887 chr17:43200129 PLCD3 0.0000022 0.1533679
59 hs_ohminp_madj_Log2 OH-MiNP Phthalates 17q21.31 Variance cg18051346 chr17:43238278 HEXIM2;HEXIM2 0.0129852 0.0164671
69 hs_pcb170_madj_Log2 PCB 170 OCs 17q21.31 Variance cg04512931 chr17:43341971 LOC100133991;MAP3K14;LOC100133991 0.0020775 0.0256931
Enrichment analysis for variance differentially methylated (VDM) genes using genotype-environment interaction for inversion 17q21.31. A) Results for the enrichment using DisGeNET database; B) GO enrichment results.

Figure 44: Enrichment analysis for variance differentially methylated (VDM) genes using genotype-environment interaction for inversion 17q21.31
A) Results for the enrichment using DisGeNET database; B) GO enrichment results.

3.2 Inversion - CpG methylation - Gene expression mediation

Table 33 summarizes the mediations of inversion - gene expression by the methylation of CpG sites.


Table 33: Significant mediations between genomic inversions and variance differentially expressed genes mediated by variance differentially methylated CpG sites.
Inversion Transcript Location.Transcript Symbol.Transcript CpG Location.CpG Symbol.CpG p.value.mediation Prop.Mediated p.value.prop.mediated
27 8p23.1 TC08000093.hg.1 chr8:11653082-11696818 FDFT1 cg02840367 chr8:11660030 FDFT1 0.047 0.1889366 0.002
151 16p11.2 TC16000994.hg.1 chr16:28853732-28857729 TUFM;MIR4721 cg09046979 chr16:28333134 SBK1 0.005 0.1538787 0.010

3.3 Impact of the pregnancy exposome on the CpG methylation

The pregnancy exposures that have an impact (p<0.001) on variance differentially methylated CpG sites are displayed in Table 34.


Table 34: Significant associations between pregnancy exposure levels and methylation of individual variance differentially methylated CpG sites.
CpG Location.CpG Symbol.CpG Exposure Exposure.abreviation p.value FDR
87 cg26670620 chr8:12244544 FAM66A hs_pfos_m_Log2 PFOS 0.0003151 0.4283069
1222 cg04025970 chr8:8727303 MFHAS1 h_distinvnear1_preg_Log Inverse distance to nearest road 0.0003760 0.4283069
2139 cg00115954 chr8:11536551 hs_zn_m_Log2 Zn 0.0001062 0.3924227
3230 cg11302791 chr8:10635419 PINX1 hs_mibp_madj_Log2 MiBP 0.0004505 0.4283069
3840 cg11465442 chr8:11832261 DEFB136 h_ndvi100_preg_None NDVI (100 m) 0.0009214 0.7457064
4648 cg08196601 chr8:12869553 C8orf79 hs_tl_mdich_None Thallium 0.0003573 0.4283069
5659 cg01378222 chr16:28622494 SULT1A1 hs_pcb118_madj_Log2 PCB 118 0.0000598 0.3924227
6653 cg22433210 chr17:43662623 hs_ddt_madj_Log2 DDT 0.0003238 0.4283069
6785 cg01882395 chr17:43717810 C17orf69 hs_prpa_madj_Log2 PRPA 0.0001376 0.3924227
6855 cg03954353 chr17:43715162 C17orf69;MGC57346 hs_mepa_madj_Log2 MEPA 0.0004236 0.4283069

3.4 Association between VDE genes and VDM CpG sites with human traits

The MDE genes and MDM CpG sites that are associated with human traits (p<0.01) are shown in Table 35 for inversion 8p23.1, and in Table 36 for inversion 17q21.31. There are not features associated with phenotypes for inversion 16p11.2.


Table 35: Variance differentially expressed genes and variance differentially methylated CpG sites from inversion 8p23.1 associated with obesity-related and neurological human traits.
Inversion Type_analysis Feature Diff Location Gene_Symbol Type_phenotype Phenotype Phenotype_abrev p.value
252 8p23.1 Variance cg06952801 G*E chr8:10460235 Obesity-related e3_pi_None Ponderal index 0.0031452
269 8p23.1 Variance cg18718312 G*E chr8:11772119 Obesity-related hs_phospho_c_None Phospholipids 0.0027903
281 8p23.1 Variance cg22651416 G*E chr8:10643634 PINX1 Obesity-related hs_phospho_c_None Phospholipids 0.0058001

Table 36: Variance differentially expressed genes and variance differentially methylated CpG sites from inversion 17q21.31 associated with obesity-related and neurological human traits.
Inversion Type_analysis Feature Diff Location Gene_Symbol Type_phenotype Phenotype Phenotype_abrev p.value
694 17q21.31 Variance cg19943578 G chr17:43483527 ARHGAP27 Neurological hs_accuracy_numeros3 Percentage of correct responses (hits and correct rejections) numbers 3-back 0.0019711
774 17q21.31 Variance cg27503360 G chr17:43890749 CRHR1 Neurological hs_accuracy_numeros3 Percentage of correct responses (hits and correct rejections) numbers 3-back 0.0072822